Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model.

BACKGROUND: Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM: To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS: The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS: The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION: Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.

Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy.

Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.

The Remission Rate of Type 2 Diabetes Outpatients with Premixed Insulin: The Result of a 5-Year Prospective Study.

The aim of the study was to evaluate the remission rate with short-term premixed insulin therapy in newly diagnosed type 2 diabetes outpatients and investigate predictors contributing to the remission rate. A 5-year prospective study was conducted with a total of 170 patients enrolled. Patients were treated with premixed insulin monotherapy or insulin in combination with one or two oral drugs. After glucose levels were well controlled, insulin and oral drugs were discontinued in a stepwise manner. The prolonged and partial remission rates were calculated and the possible factors contributing to remission were also analyzed. A total of 164 subjects completed the research study. The prolonged remission, partial remission and non-remission rates at the 5-year follow-up were 9.8, 59.8, and 30.5%, respectively. The remission rate was negatively correlated with disease duration (r=0.39). The combined rate of remission (prolonged and partial remission) significantly decreased when the duration was longer than 16 days, and reduced to approximately 50% after 1 month. Moreover, 75% of prolonged remission patients had duration of < 16 days. At the 5-year follow-up, the prolonged remission rate was 9.8% and the partial remission rate was 59.8%. Furthermore, the duration after diagnosis is an independent predictor of remission rate, and initiation of short-term premixed insulin therapy within the first 16 days of diabetes diagnosis is very important for remission. This is the first study to evaluate the remission rate associated with short-term premixed insulin therapy in recently diagnosed type 2 diabetes outpatients. At the 5-year follow-up, the prolonged remission rate was 9.8% and the partial remission rate was 59.8%. The duration of diabetes was identified as an independent predictor of drug-free remission. The initiation of short-term premixed insulin therapy within 15 days of diabetes onset is particular importance for remission.

Construction and biocompatibility of a thin type I/II collagen composite scaffold.

Articular cartilage injury is a common type of damage observed in clinical practice. A matrix-induced autologous chondrocyte implant was developed to repair articular cartilage as an advancement on the autologous chondrocyte implant procedure. Here, we establish a thin double layer of collagen as a novel and effective bioscaffold for the regeneration of cartilaginous lesions. We created a collagen membrane with double layers using a cover slip, a cover slip, and the collagen was then freeze-dried under vacuum. Carbodiimide as a crosslinking agent was used to obtain a relatively stable collagen construction. The thickness of the knee joint cartilage from grown rabbits was measured from a frozen section. Both type I and type II collagens were characterized using Sodium dodecylsulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ultraviolet absorption peaks. The aperture size of the scaffold was observed using a scanning electron microscope (SEM). The degradation of the scaffolds in vitro was tested through digestion using collagenase solution. The mechanical capacity of the scaffolds was assessed under dynamic compression. The influence of the scaffold on chondrocyte proliferation was assessed using the methyl thiazolyl tetrazolium (MTT) colourimetric assay and scanning electron microscopy. The frozen sections of the rabbit femoral condyle showed that the thickness of the weight-bearing area of the articular cartilage was less than 1 mm. The results of the SDS-PAGE and ultraviolet absorption peaks of the collagens were in agreement with the standard photographs in the references. SEM showed that the aperture size of the cross-linked scaffold was 82.14 ± 15.70 µm. The in vitro degradation studies indicated that Carbodiimide cross-linking can effectively enhance the biostability of the scaffolds. The Carbodiimide cross-linking protocol resulted in a mean value for the samples that ranged from 8.72 to 15.95 MPa for the compressive strength. The results of the MTT demonstrated that the scaffold had promoted chondrocyte proliferation and SEM observations showed that the scaffold was a good adhesive and growth material for chondrocytes. Thin type I/II collagen composite scaffold can meet the demands of cartilage tissue engineering and have good biocompatibility.

Calcium Dobesilate Prevents Diabetic Kidney Disease by Decreasing Bim and Inhibiting Apoptosis of Renal Proximal Tubular Epithelial Cells.

Apoptosis of renal proximal tubular epithelial cells (PTECs) plays a vital role in the pathogenesis and progression of diabetic kidney disease (DKD). Calcium dobesilate is a vascular protective compound used for treatment of diabetic retinopathy and chronic venous insufficiency. The aim of this study was to determine whether calcium dobesilate can protect PTECs from glucose-induced apoptosis and the potential mechanism of this effect. It is indicated that high glucose promoted abnormal apoptosis of HK2 cells, which was inhibited by treatment of calcium dobesilate, while Bim expression decreased in response to calcium dobesilate in high-glucose-treated HK2 cells. These findings confirmed the therapeutic effects of calcium dobesilate on DKD and emphasized the importance of it as a potentially crucial drug in treatment of DKD.

Expression of Pax8 is decreased and bortezomib does not increase the iodine uptake in thyroid carcinoma cells.

Fundamental treatment for papillary thyroid carcinoma (PTC) involves total or subtotal thyroidectomy. Iodine-131 ((131)I) is routinely utilized to target remnant thyroid cancer and metastasis after thyroidectomy. The effectiveness of other therapeutic modalities remains unsatisfactory; thus, these patients have a poor prognosis. The manner in which the ability of (131)I uptake can be improved is vital for their prognosis. Bortezomib has been used as a re-differentiation agent for the treatment of patients with multiple myeloma; however, little is reported about the role of bortezomib in thyroid cancer. To evaluate the therapeutic potential of bortezomib in a human PTC cell line, expression of paired-box 8 (Pax8) protein was determined using Western blot in PTC, normal thyroid, and anaplastic/undifferentiated thyroid carcinoma (ATC) cells. The expression of Pax8 protein in PTC cells pretreated with bortezomib was determined using the same method. Iodine uptake was determined using (131)I radioactivity assay. The level of Pax8 protein in normal thyroid cells was significantly higher than in PTC (P < 0.05) and ATC cells (P < 0.05); its expression in PTC cells was also significantly higher than in ATC cells (P < 0.05). The PTC cells in the bortezomib-treated group showed a higher expression of Pax8 protein than the control group (P < 0.05). These findings indicate that bortezomib can increase the expression of Pax8, but does not significantly increase the iodine uptake of PTC cells.

[Effects of Acupuncture on Neurofunction and Neuropsychological Factors of Chronic Alcoholic Peripheral Neuropathy Patients].

OBJECTIVE: To observe the effects of acupuncture on neurofunction and neuropsychological factors of chronic alcoholic peripheral neuropathy (CAPN) patients. METHODS: Totally 120 CAPN patients were assigned to the common treatment group, acupuncture group A, and acupuncture group B according to random digit table, 40 in each group. All patients recieved conventional drug therapy. Besides, patients in the acupuncture group A were additionally needled at Pishu (BL20), Weishu (BL21), Xuehai (SP10), Yinlingquan (SP9), Zusanli (ST36), Yanglingquan (GB34), Jiexi (ST41), Xuanzhong (GB39), Xiangu (ST43),Taixi (KI3), Quchi (LI11), Waiguan (SJ5), Hegu (LI4), and so on. On these bases patients in the acupuncture group B were needled at Sishencong (EX-HN1), Yintang (EX-HN3), Neiguan (PC6), Taichong (LR3), Sanyinjiao (SP6), and Taiyang (EX-HN5). Acupuncture was performed once a day, 14 times as a course; and then once on every other day, 14 times in total for 4 weeks. All treatment lasted for 8 successive weeks. Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Neurological Severity Score (NSS), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) were assessed, motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) were detected before and after treatment. RESULTS: After 8 weeks of treatment the scores of NIS-LL and NSS significantly decreased in the 3 groups, with statistical difference as compared with before treatment (P < 0.05). Scores of NIS-LL and NSS decreased more in acupuncture groups A and B than in the common treatment group (P < 0.05), and more obvious in acupuncture group B (P < 0.05). Compared with the same group before treatment, MCV and SCV of median nerve, ulnar nerve, common peroneal nerve and tibial nerve increased in acupuncture treatment group A and B after 8-week treatment (P < 0.05). MCV of median nerve, MCV and SCV of common peroneal nerve and tibial nerve significantly increased in the common treatment group (P < 0.05). Compared with the common treatment group, SCV of median nerve, MCV and SCV of ulnar nerve, common peroneal nerve and tibial nerve obviously increased in acupuncture treatment groups A and B after treatment (P < 0.05). MCV of ulnar nerve, MCV and SCV of common peroneal nerve and tibial nerve obviously increased more in acupuncture treatment group A than in acupuncture treatment group B (P < 0.05). At week 8 after treatment scores of HAMD and HAMA were obviously lowered in acupuncture groups A and B, with statistical difference as compared with before treatment (P < 0.05). The scores of HAMD were also decreased in the common treatment group, as compared with before treatment (P < 0.05). At week 8 after treatment scores of HAMD and HAMA were obviously lowered more in acupuncture treatment group B than in acupuncture treatment group A (P < 0.05). CONCLUSION: Acupuncture therapy could effectively improve the neurofunction of CAPN patients, and improve complicated anxiety and depression by additionally needling at Sishencong (EX-HN1), Yintang (EX-HN3), Taichong (LR3), Sanyinjiao (SP6), and Taiyang (EX-HN5).

Autologous bone marrow stem cell transplantation in critical limb ischemia: a meta-analysis of randomized controlled trials.

BACKGROUND: Amputation-free survival (AFS) has been recommended as the gold standard for evaluating No-Option Critical Limb Ischemia (NO-CLI) therapy. Early-phase clinical trials suggest that autologous bone-marrow derived cells (BMCs) transplantation may have a positive effect on patients with NO-CLI, especially decreasing the incidence of amputation. However, the BMCs therapeutic efficacy remains controversial and whether BMCs therapy is suitable for all CLI patients is unclear. METHODS: We conducted a meta-analysis using data from randomized controlled trials (RCTs) by comparing autologous BMCs therapy with controls in patients with critical limb ischemia, and the primary endpoint is the incidence of amputation. Pubmed, EBSCO and the Cochrane Central Register of Controlled Trials (to approximately July 25, 2012) were searched. RESULTS: Seven RCTs with 373 patients were enrolled in the meta-analysis. Because serious disease was the main reason leading to amputation in one trial, six studies with 333 patients were finally included in the meta-analysis. Pooling the data of the final six studies, we found that BMCs therapy significantly decreased the incidence of amputation in patients with CLI (odds ratio (OR), 0.37; 95% confidence interval (CI), 0.22 to 0.62; P = 0.0002), and the efficacy had not significantly declined within 6 months after BMCs were transplanted; OR, 0.33; 95%CI, 0.16 to 0.70; P = 0.004 within 6 months and OR, 0.30; 95%CI, 0.11 to 0.79; P = 0.01 within 3 months. The rate of AFS after BMCs therapy was significantly increased in patients with Rutherford class 5 CLI (OR 3.28; 95%CI, 1.12 to 9.65; P = 0.03), while there was no significant improvement in patients with Rutherford class 4 (OR 0.35; 95%CI, 0.05 to 2.33; P = 0.28) compared with controls. The BMCs therapy also improved ulcer healing (OR, 5.83; 95%CI, 2.37 to 14.29; P = 0.0001). CONCLUSIONS: Our analysis suggests that autologous BMCs therapy has a beneficial effect in decreasing the incidence of amputation and the efficacy does not decrease significantly within 6 months after BMCs transplantation. Patients with Rutherford class 5 are suitable for BMCs therapy, while the efficiency in patients with Rutherford 4 needs further evaluation.

[Influences of nevirapine on cell proliferation and expression of sodium/iodide symporter in human anaplastic thyroid carcinoma cell line].

OBJECTIVE: To explore the effects of nevirapine on the proliferation and expression of sodium-iodide symporter (NIS) mRNA in FRO cells in vitro. METHODS: The cells were incubated in different concentrations of nevirapine to evaluate the cell growth rate. And the expressions of NIS mRNA and TSHR mRNA were determined by real-time quantitative reverse polymerase chain reaction. RESULTS: Cell proliferation was inhibited after a 96 h nevirapine treatment. After incubating in the presence of 200 and 350 µmol/L nevirapine, the expression of NIS mRNA was (1.39 ± 0.04) and (1.85 ± 0.28) times versus the control cells (P < 0.01) while the expressions of TSHR mRNA was (2.23 ± 1.47) and (2.83 ± 0.78) times versus the control cells respectively (both P < 0.05). CONCLUSION: Nevirapine inhibits cell proliferation in FRO cell line. More importantly, the cells exposed to nevirapine may induce the up-regulations of NIS mRNA and TSHR mRNA.

Posterolateral spinal fusion with nano-hydroxyapatite-collagen/PLA composite and autologous adipose-derived mesenchymal stem cells in a rabbit model.

Spinal fusion is routinely performed to treat low back pain caused by degeneration of intervertebral discs. An autologous bone graft derived from the iliac crest is the standard procedure used for spinal fusion. However, several shortcomings, including pseudarthrosis, pain and the need for blood transfusion are known to be associated with the procedure. Our study analysed the effectiveness of a new mineralized collagen matrix, nano-hydroxyapatite-collagen-polylactic acid (nHAC-PLA), combined with autologous adipose-derived mesenchymal stem cells (ADMSCs) as a graft material for posterolateral spinal fusion in a rabbit model. Forty rabbits were randomly divided into four groups: autologous iliac crest bone group (ACB), nHAC-PLA composite group (nHAC-PLA), autologous iliac crest bone mixed with nHAC-PLA composite group (ACB + nHAC-PLA), and nHAC-PLA composite combined with ADMSCs (ADMSCs + nHAC-PLA). The viability and the proliferation of the ADMSCs seeded on the scaffolds were evaluated by live/dead kit and MTT assay in vitro, respectively. Lumbar posterolateral fusions were assessed by manual palpation, radiographical and histological procedures, mechanical strength and scanning electronic microscopy (SEM) in 10 weeks of observation. The results showed that the rate of fusion was significantly higher in the ACB and ADMSCs + nHAC-PLA groups than that in the nHAC-PLA and ACB + nHAC-PLA groups. It was not significantly higher in the ACB group than in the ADMSCs + nHAC-PLA group. From microstructural analysis of the samples using histological staining methods, there was more new bone-like tissue formation in the ACB and ADMSCs + nHAC-PLA groups than that in the other two groups at the 10th postoperative week. Our study demonstrated the effective impact of nHAC-PLA combined with ADMSCs in rabbit posterolateral spinal fusion.

Evaluation of a risk factor scoring model in screening for undiagnosed diabetes in China population.

OBJECTIVE: To develop a risk scoring model for screening for undiagnosed type 2 diabetes in Chinese population. METHODS: A total of 5348 subjects from two districts of Jinan City, Shandong Province, China were enrolled. Group A (2985) included individuals from east of the city and Group B (2363) from west of the city. Screening questionnaires and a standard oral glucose tolerance test (OGTT) were completed by all subjects. Based on the stepwise logistic regression analysis of Group A, variables were selected to establish the risk scoring model. The validity and effectiveness of this model were evaluated in Group B. RESULTS: Based on stepwise logistic regression analysis performed with data of Group A, variables including age, body mass index (BMI), waist-to-hip ratio (WHR), systolic pressure, diastolic pressure, heart rate, family history of diabetes, and history of high glucose were accepted into the risk scoring model. The risk for having diabetes increased along with aggregate scores. When Youden index was closest to 1, the optimal cutoff value was set up at 51. At this point, the diabetes risk scoring model could identify diabetes patients with a sensitivity of 83.3% and a specificity of 66.5%, making the positive predictive value 12.83% and negative predictive value 98.53%. We compared our model with the Finnish and Danish model and concluded that our model has superior validity in Chinese population. CONCLUSIONS: Our diabetes risk scoring model has satisfactory sensitivity and specificity for identifying undiagnosed diabetes in our population, which might be a simple and practical tool suitable for massive diabetes screening.

[Association of coxsackie virus infection and T lymphocyte subset changes with type 1 diabetes].

OBJECTIVE: To investigate the relationship between coxsackievirus infection and type 1 diabetes mellitus (T1DM), and observe the changes of T lymphocyte subsets in the development of T1DM. METHODS: We detected Coxsackievirus RNA by reverse transcription PCR, and measured the change in T-lymphocyte subsets by flow cytometry in 22 cases of newly diagnosed T1DM (group I), 30 patients with diabetes for some time (group II), and 30 healthy subjects (group III). RESULTS: The positivity rate of coxsackie virus RNA in groups I, II, and III was 55.55%, 23.33%, and 6.67%, respectively, showing a significant difference among the 3 groups (P<0.01). Patients with upper respiratory tract infection had a higher positivity rate for coxsackie virus RNA than those without upper respiratory tract infection in group I (P<0.05). Compared with the control group, the percentage of CD3, CD4 and CD4/CD8 ratio decreased significantly in groups I and II (P<0.01 or P<0.05). CD3, CD4 and CD4/CD8 tended to increase in group II in comparison with group I, and there was an significant difference in CD3 and CD4 between the two groups (P<0.01 or P<0.05). Compared with the control group and CVBRNA-negative group, CVBRNA-positive group showed significantly lowered CD3, CD4, CD8 and CD4/CD8 (P<0.01 or P<0.05). CONCLUSION: The occurrence and development of type 1 diabetes is closely related to coxsackie virus infection, and the changes in T lymphocyte subsets serves as a probable mechanism of its pathogenicity.

[Experimental study on the prevention of epidural scar adhesion with polycaprolactone/polylactic acid membrane].

OBJECTIVE: To evaluate the ability of a polycaprolactone/polylactic acid (PCL/PLA) membrane to inhibit epidural scar adhesion after laminectomy, and observe the responsive changes of the pain media in the spinal cord. METHODS: L(1), L(3) laminectomies were performed on 96 Wistar rats. The rats were divided into 3 groups: None-implant Control Group (NC), Autologous free fat graft group (AFFG) and PCL/PLA membrane group (PCL/PLAm). The rats were killed at 1, 3, 6, and 12 weeks postoperatively. Epidural scar formation and adhesion were observed grossly and histologically. Reverse transcription polymerase chain reaction (RT-PCR) were used to analyses the expression of Transforming growth factor beta (TGF-beta) in the epidural scar. Immunohistochemistry stain and RT-PCR were performed to evaluate the expression of the substance P and the c-fos gene in the relevant spinal cord, and the results were analyzed statistically. RESULTS: Gross evaluation and histological evaluation showed that in the NC lamina defect site had much scar tissue and had wide and tight adhesions to the dura; in the AFFG, with the fat degrading gradually, the adhesions were increased; whereas in the PCL/PLAm group, there were slightly adhesions to the dura. RT-PCR showed that the expression of the TGF-beta was much less in the PCL/PLAm group than in the NC group. The insertion of the PCL/PLA membrane and the fat patch reduced the expression of the substance P and the c-fos gene in the spinal cord. CONCLUSION: The insertion of the PCL/PLA membrane reduces scar formation and separates fibrosis tissue from the dura, the results indicate that PCL/PLA membrane is an effective way of reducing peridural scar formation and preventing the failed back surgery syndrome.