A whole-slide foundation model for digital pathology from real-world data.

Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles1-3. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context4. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet5 method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data6. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology7,8 by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.

An evaluation index system for regional mobile SARS-CoV-2 virus nucleic acid testing capacity in China: a modified Delphi consensus study.

BACKGROUND: Large-scale detection has great potential to bring benefits for containing the COVID-19 epidemic and supporting the government in reopening economic activities. Evaluating the true regional mobile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus nucleic acid testing capacity is essential to improve the overall fighting performance against this epidemic and maintain economic development. However, such a tool is not available in this issue. We aimed to establish an evaluation index system for assessing the regional mobile SARS-CoV-2 virus nucleic acid testing capacity and provide suggestions for improving the capacity level. METHODS: The initial version of the evaluation index system was identified based on massive literature and expert interviews. The Delphi method questionnaire was designed and 30 experts were consulted in two rounds of questionnaire to select and revise indexes at all three levels. The Analytic Hierarchy Process method was used to calculate the weight of indexes at all three levels. RESULTS: The evaluation index system for assessing the regional mobile SARS-CoV-2 virus nucleic acid testing capacity, including 5 first-level indexes, 17 second-level indexes, and 90 third-level indexes. The response rates of questionnaires delivered in the two rounds of consultation were 100 and 96.7%. Furthermore, the authority coefficient of 30 experts was 0.71. Kendall's coordination coefficient differences were statistically significant (P < 0.001). The weighted values of capacity indexes were established at all levels according to the consistency test, demonstrating that 'Personnel team construction' (0.2046) came first amongst the five first-level indexes, followed by 'Laboratory performance building and maintenance' (0.2023), 'Emergency response guarantee' (0.1989), 'Information management system for nucleic acid testing resources' (0.1982) and 'Regional mobile nucleic acid testing emergency response system construction' (0.1959). CONCLUSION: The evaluation system for assessing the regional mobile SARS-CoV-2 virus nucleic acid testing capacity puts forward a specific, objective, and quantifiable evaluation criterion. The evaluation system can act as a tool for diversified subjects to find the weak links and loopholes. It also provides a measurable basis for authorities to improve nucleic acid testing capabilities.

Effects of maternal and fetal vascular endothelial growth factor a single nucleotide polymorphisms on pre-eclampsia: A hybrid design study.

Maternal and fetal gene variants play important roles in the pathology of pre-eclampsia (PE), but most studies investigating the associations between vascular endothelial growth factor A (VEGF-A) gene variates and PE focusing on maternal genetic effects. The present study firstly used a hybrid case-parent and control-mother study design investigating the both maternal and fetal effects of VEGF-A gene polymorphisms on PE among Han Chinese pregnant women. This study recruited 221 PE patients with their partners and infants and 345 normotensive women with their infants. The current study found that, in both maternal and fetal dominant model (GC + CC/GG), VEGF-A rs2010963 polymorphism was associated with an increased risk of PE (OR = 1.85, 95% CI: 1.25-2.75; OR = 1.90, 95% CI: 1.28-2.83, respectively). In the log-liner model analyses, offspring carrying the genotype of GC or CC in the rs2010963 polymorphism could increase the risk of maternal PE (OR = 1.84, 95%CI: 1.18-2.86; OR = 1.89, 95%CI: 1.02-3.49, respectively) compared to the offspring with GG. Meanwhile, the present study also found that passive smoking had a significant interaction with maternal rs2010963 polymorphism (PLRT = 0.022) on the risk of PE.

[Radical retropubic prostatectomy for prostate cancer with pelvic lymph node metastasis].

OBJECTIVE: To investigate the safety and effectiveness of radical retropubic prostatectomy (RRP) with adjuvant androgen deprivation or external radiotherapy in the treatment of prostate cancer (PCa) with pelvic lymph node metastasis (PLNM). METHODS: Twenty PCa patients underwent bilateral pedal lymphangiography (PLG) preoperatively, and 11 of them received lymph node aspiration for examination of the mRNA expressions of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) in the lymph fluid by real-time RT-PCR. All the patients were treated by RRP with extended dissection of pelvic lymph nodes, and 3 of them by external radiotherapy in addition after recovery from urinary incontinence because of positive surgical margins, followed by adjuvant androgen deprivation therapy. RESULTS: Real-time RT-PCR showed positive mRNA expressions of PSA and PSMA in the lymph fluid of the 11 patients, all pathologically confirmed with PLNM. The median intraoperative blood loss was 575 ml, with blood transfusion for 5 cases. Positive surgical margin was found in 3 cases, lymphorrhagia in 2 and urinary leakage in another 2 each. There were no such severe complications as vascular injury and rectum perforation. The patients were followed up for 6－48 (mean 42) months, during which, biochemical recurrence was observed in 12 cases at a median of 12 months postoperatively and 2 patients died at 12 and 48 months respectively. CONCLUSIONS: Bilateral PLG and lymph node aspiration for examination of the mRNA expressions of PSA and PSMA in the lymph fluid help to confirm PLNM preoperatively. Radical retropubic prostatectomy with adjuvant androgen deprivation or external radiotherapy is safe and effective for the treatment of PCa with PLNM, but it should be chosen cautiously for those with Gleason 5+5.

C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling.

Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP-activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1α downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling.

Right-Crossed, Fused Renal Ectopia L-Shaped Kidney Type with Urinary Chyluria.

Crossed fused renal ectopia combined with chyluria is extremely rare. Here we report the case of a patient who was admitted to our institution since milky urine and was finally found to have an L-shaped fused kidney and renal pelvis fistula. The patient was cured by renal pelvic instillation sclerotherapy.

The advantages of unilateral pedal lymphography in the diagnosis of chyluria.

OBJECTIVES: To evaluate the efficacy and safety of pedal lymphography (PLG) in the localization diagnosis of chyluria. METHODS: Cystoscopy was performed in 153 patients and PLG in 121 cases. Unilateral or staged bilateral ligation and stripping of renal lymphatic vessel were performed according to the results of cystoscopy and/or PLG. RESULTS: Unilateral and bilateral urinary excretion of chyle was detected in 123 and 1 case by cystoscopy, respectively. In 121 cases receiving PLG, 100 cases of unilateral fistulous connection between the renal pelvis and the lymphatic system, 18 cases of bilateral fistulas and 1 case of lymphatic bladder fistula were demonstrated. PLG has a higher diagnostic rate for the detection of bilateral lymphatic renal pelvis fistulas than cystoscopy (p<0.05). 28 cases received renal pedicle lymphatic disconnection only according to the results of cystoscopy, and 3 of them failed (10.1%). While 121 cases had the same operation according to the results of PLG, only 1 case failed the operation (0.8%). CONCLUSIONS: PLG was efficient and safe for the localization diagnosis of chyluria, with a higher detection rate of bilateral fistulas than cystoscopy. PLG might benefit the selection of appropriate therapy and improve the surgical effect.

Toward structuring real-world data: Deep learning for extracting oncology information from clinical text with patient-level supervision.

Most detailed patient information in real-world data (RWD) is only consistently available in free-text clinical documents. Manual curation is expensive and time consuming. Developing natural language processing (NLP) methods for structuring RWD is thus essential for scaling real-world evidence generation. We propose leveraging patient-level supervision from medical registries, which are often readily available and capture key patient information, for general RWD applications. We conduct an extensive study on 135,107 patients from the cancer registry of a large integrated delivery network (IDN) comprising healthcare systems in five western US states. Our deep-learning methods attain test area under the receiver operating characteristic curve (AUROC) values of 94%-99% for key tumor attributes and comparable performance on held-out data from separate health systems and states. Ablation results demonstrate the superiority of these advanced deep-learning methods. Error analysis shows that our NLP system sometimes even corrects errors in registrar labels.

KLF9 inhibits the proliferation, invasion, and migration of renal cell carcinoma through the SDF-1/CXCR4 axis.

Altered Krüppel-like factor 9 (KLF9) expression can regulate the progression of several cancers, including renal cell carcinoma (RCC). This study was conducted to investigate the role of KLF9 in the proliferation, invasion, and migration of RCC cells via regulation of stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). The expression patterns of KLF9, SDF-1, and CXCR4 in the experimental cell lines were determined by real-time quantitative polymerase chain reaction and Western blotting. After transfection of the KLF9 siRNA and KLF9 pcDNA, cell proliferation, invasion, and migration were evaluated by experiments including cell counting kit-8, colony formation, and Transwell assays. The binding of KLF9 to the SDF-1 promoter was analyzed by chromatin immunoprecipitation and dual-luciferase assay. The rescue experiment was performed using the recombinant SDF-1 protein and KLF9 pcDNA. KLF9 was downregulated in the RCC cells. KLF9 knockdown induced the proliferation, invasion, and migration of RCC cells, whereas KLF9 overexpression elicited the opposite roles. Mechanically, KLF9 bound to the SDF-1 promoter, repressed SDF-1 transcription, and reduced the SDF-1/CXCR4 expression levels. Activation of the SDF-1/CXCR4 axis attenuated the inhibitory role of KLF9 overexpression in RCC cell growth. Ordinarily, KLF9 suppressed the proliferation, invasion, and migration of RCC cells by repressing the SDF-1/CXCR4 signaling.

CFTR polymorphisms of healthy individuals in two Chinese cities--Changchun and Nanjing.

BACKGROUND AND AIM: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel, cause cystic fibrosis. In order to investigate the polymorphic backgrounds of CFTR genes of healthy populations in different Chinese cities (Changchun and Nanjing), we analyzed 119 blood samples (Changchun 64, Nanjing 55) of randomly selected healthy individuals for poly T, TG-repeats and M470V polymorphisms. We analyzed the differences of CFTR polymorphic distributions between the two Chinese cities from the south and the north. Methods Genomic DNA was extracted from whole blood. DNA fragments of CFTR gene were amplified by polymerase chain reaction (PCR). Poly-T and TG repeats were directly sequenced by auto sequencer (ABI 310). M470V was detected by a HphI restriction enzyme. RESULTS: The T7 allele was the most common haplotype in Changchun (0.938) and Nanjing (0.927) populations. The T5 allele was present in only 7 Changchun and 3 Nanjing subjects. The TG11 and TG12 alleles were dominant haplotypes in Changchun (TG11 0.500, TG12 0.453) and Nanjing (TG11 0.345, TG12 0.609). The frequency of the V470 allele was 0.633 in Changchun, which was higher than that in Nanjing (0.500) (p < 0.05). There were three major haplotypes: T7-TG11-V470, T7-TG12-M470 and T7-TG12-V470. The T7-TG11-V470 was the most common haplotype in Changchun (0.514), while T7-TG12-M470 was the most common haplotype in Nanjing (0.500). CONCLUSION: Though Changchun and Nanjing are in the same country, their polymorphic backgrounds of CFTR gene are very different. Most of the two populations have genotypes that cause lower CFTR function.

[Experience in reducing intraoperative blood loss in radical retropubic prostatectomy].

OBJECTIVE: To search for an effective method of reducing intraoperative blood loss in radical retropubic prostatectomy (RRP). METHODS: We performed RRP for 100 patients with prostate cancer, 50 (group A) with the Walsh or Poor method for handling the dorsal venous complex (DVC), and the other 50 (group B) through the following three additional procedures for hemostasis: first placing a #7 prophylactic suture in the distal position of DVC, then ligating the vascular bundle of the prostatic apex with continuous 4-0 Vicryl sutures, and lastly placing a 4-0 absorbable suture followed by freeing the neurovascular bundle (NVB) or freeing NVB before suturing the remained levator ani myofascia and the deep layer of Denovilliers' fascia above the rectal serosa with 4-0 Vicryl. We assessed the effects of the three hemostatic methods in RRP by comparing the volumes of intraoperative blood loss and transfusion, operation time and perioperative levels of hemoglobin. RESULTS: There were no significant differences between groups A and B in age, PSA, Gleason score, clinical stage, prostate volume, operation time and perioperative hemoglobin levels (P>0.05). The volumes of intraoperative blood loss and transfusion were markedly higher in group A ([1103.00 +/- 528.03] ml and [482.00 +/- 364.60] ml) than in B ([528.00 +/- 258.96] ml and [140.00 +/- 266.28] ml) (P<0.05). CONCLUSION: Intraoperative blood loss in RRP could be significantly decreased by placing a prophylactic hemostatic suture in the distal position of DVC, continuous suture of the vascular bundle of the prostatic apex after cutting off the urethra, and placing a fine absorbable suture above NVB or continuous suture of the remained levator ani mony fascia and the deep layer of Denovilliers'fascia above the rectal serosa with absorbable sutures after freeing NVB.

Association Between Water Intake and Mortality Risk-Evidence From a National Prospective Study.

Background: Few studies have explored the association between water intake and mortality risk, and the findings were inconsistent. Objective: This study aimed to explore the water intake-mortality association, utilizing the data from the National Health and Nutrition Examination Survey (NHANES) and the 2015 public-linked mortality files released by the National Center for Health Statistics. Methods: We used the diet- and mortality-linked data of a total of 35,463 adults (17,234 men) aged ≥20 years in the NHANESs 1999-2014 to perform a prospective study. The multivariate-adjusted Cox proportional hazards model was used to explore the associations of the amount of water intake (expressed by total water, plain water, beverage, and food water) and water intake proportion (expressed by the percentage of each kind of water) with mortality risks due to all causes, malignant neoplasms/cancer, and heart disease. The restricted cubic spline plots were adopted to clarify the dose-response relationships among them. Results: With a median of 88 months (interquartile range: 49-136 months) follow-up, a total of 4,915 all-cause deaths occurred, including 1,073 and 861 deaths from malignant neoplasms/cancer and heart disease, respectively. The amount of water intake in either type was negatively associated with all-cause mortality risk. Additionally, the negative linear dose-response relationships of water intake and all-cause mortality risk were found for all types of water except for food water, which followed a non-linear pattern. Similarly, compared to the lowest quartile (beverage water intake: <676 g/day; food water intake: <532 g/day), beverage and food water intakes in the range of 1,033-1,524 and 1,612-3,802 g/day were associated with decreased malignant neoplasms/cancer mortality risk. A U-shaped dose-response relationship was found for beverage water intake and malignant neoplasms/cancer mortality risk and a negative linear dose-response relationship was found for food water intake and malignant neoplasms/cancer mortality risk. Coffee and/or tea consumption was/were negatively associated with mortality risks due to all causes and malignant neoplasms/cancer. No significant associations of water intake proportion and mortality risks were found. Conclusion: Our findings demonstrated that higher water intake is associated with lower mortality risks among the United States population.

Multiple vitamin co-exposure and mortality risk: A prospective study.

BACKGROUND & AIMS: Existing epidemiological studies explored the associations of circulating vitamins and mortality focusing on individual vitamin effects, and controversial findings were obtained. The joint effects of multiple vitamin co-exposure are worth studying. The study aimed to elucidate the associations of circulating vitamins and the joint effects of these vitamins' co-exposure with all-cause and cause-specific mortality risks. METHODS: We prospectively evaluated the associations of the concentrations of six kinds of vitamins (A, D, E, C, B12 and B9) in serum with risks for all-cause and cause-specific mortalities among U.S. adults. Mortality status and cause of death were determined by NHANES-linked public available files dated up to 31 December 2015. An unsupervised K-means clustering method was used to cluster the participants into several vitamin co-exposure patterns. The Cox proportional hazards model was used for statistical analysis. RESULTS: A total of 1404 deaths occurred during a median of 10.9 years follow-up among 8295 participants. In multivariable adjustment, increasing levels of vitamin D were associated with reduced all-cause and cause-specific mortality risks. A J-shaped nonlinear exposure-response relationship was observed between all studied vitamins (except for vitamin D) and all-cause mortality risk. Four co-exposure patterns were generated based on the studied vitamins, as follows: low-level exposure (cluster 1), vitamin A/D exposure (cluster 2), water-soluble vitamin exposure (cluster 3) and high-level exposure (cluster 4). Compared with those in cluster 1, participants in cluster 2 had lower all-cause and cancer mortality risks, with hazard ratios (95% confidence intervals [CIs]) of 0.67 (0.53, 0.85) and 0.45 (0.29, 0.71), respectively. CONCLUSIONS: The findings in this study indicated that high circulating vitamin D levels were associated with reduced mortality risk among U.S. adults. Vitamin co-exposure at moderate levels appropriately contributed to low all-cause and cancer mortality risks. Our findings provided a novel perspective for exploring the joint health effects of multivitamin co-exposure. Future investigations are needed to further unravel the underlying mechanisms of possible vitamin interactions.

Association between SEMA3A signaling pathway genes and BMD/OP risk: An epidemiological and experimental study.

Objective: This study aimed to explore the associations of genetic variants in the semaphorin 3A (SEMA3A) signaling pathway genes, including SEMA3A, NRP1, PLXNA1, PLXNA2 and PLXNA3 with osteoporosis (OP) risk and bone mineral density (BMD) in a Chinese Han older adult population. Study design and method: A two-stage design was adopted. Total of 47.8kb regions in the 5 genes were sequenced using targeted next-generation sequencing (NGS) technology in the discovery stage, and the discovered OP-related single nucleotide polymorphisms (SNPs) were further genotyped using improved multiple linkage detection reaction technique in the validation stage. Methods of ALP/TRAP staining, real-time fluorescent quantitative PCR, and cell proliferation and apoptosis assays were performed with MC3T3-E1 and RAW 264.7 cell lines to clarify biological effects of observed functional variants in cell lines responsible for bone mass remodeling. Results: Total of 400 postmenopausal women (211 OP cases) were involved in the discovery stage, where 6 common and 4 rare genetic variants were found to be associated with OP risk. In the validation stage among another 859 participants (417 women, 270 OP cases), the PLXNA2 rs2274446 T allele was associated with reduced OP risk and increased femoral neck (FN) BMD compared to the C allele. Moreover, significant associations of NRP1 rs2070296 with FN BMD/OP risk and of NRP1 rs180868035 with lumbar spine and FN BMDs were also observed in the combination dataset analysis. Compared to the osteoblasts/osteoclasts transfected with the wild-type NRP1 rs180868035, those transfected with the mutant-type had reduced mRNA expression of osteoblastic genes (i.e., ALP, RUNX2, SP7 and OCN), while elevated mRNA expression of osteoclastic genes (i.e., TRAP, NFATc1 and CTSK). Furthermore, mutant NRP1 rs180868035 transfection inhibited osteoblast proliferation and osteoclast apoptosis, while promoted osteoclast proliferation and osteoblast apoptosis in corresponding cell lines. Conclusion: Genetic variants located in NRP1 and PLXNA2 genes were associated with OP risk and BMD. The NRP1 rs180868035 affects bone metabolism by influencing osteoblasts and osteoclasts differentiation, proliferation and apoptosis.

Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects.

Trinucleotide repeat containing 9 (TNRC9) is a gene located at chromosome 16q12. Although of an uncertain function, it is a newly described risk factor for breast cancer. It contains a putative high-mobility group box motif, suggesting its possible role as transcription factor; it has been implicated in breast cancer metastasis. Published studies on the association between TNRC9 polymorphisms and breast cancer risk remain inconclusive, and a meta-analysis is required to verify the association. This pioneering research performed a meta-analysis of eight studies comprising a total of 25,828 cases and 36,177 controls. Significantly elevated breast cancer risk was associated with TNRC9 rs3803662 polymorphism when all studies were pooled in the meta-analysis (T vs. C allele contrast model: OR 1.18, 95% CI 1.09-1.28; TT vs. CC homozygote codominant model: OR 1.26, 95% CI 1.02-1.55; TT vs. CC+CT recessive model: OR 1.23, 95% CI 1.06-1.42). For TNRC9 rs12443621 polymorphism, no significant association was detected in all genetic models. For TNRC9 rs12443621 polymorphism, meanwhile, no significant association was observed in all comparison models. Conclusively, this meta-analysis suggests that TNRC9 rs3803662 polymorphism was significantly correlated with breast cancer risk and the variant T allele of TNRC9 rs3803662 polymorphism is a low-penetrant risk factor for developing breast cancer. There is no significant association between TNRC9 rs12443621 and rs8051542 polymorphisms and risk of breast cancer in current literature.

Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a meta-analysis.

Previous epidemiological studies have evaluated the association between the ABCB1 polymorphism and the risk of breast cancer with conflicting results. Hence, we conducted a meta-analysis of the ABCB1 gene and risk of breast cancer to obtain the most reliable estimate of the association. PubMed, Embase, and Web of Science databases were searched. A total of eight studies including 3,829 cases and 6,193 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of associations between the ABCB1 C3435T and rs2214102 G>A polymorphisms and risk of breast cancer. Of these studies, only one deviated from Hardy-Weinberg equilibrium. Summary estimates indicated that the ABCB1 C3435T polymorphism was not associated with increased risk of breast cancer in the allele contrast model (T vs. C, pooled OR = 1.15; 95% CI = 0.89-1.48); the co-dominant model (CT vs. CC, OR = 1.12 [0.86-1.46] and TT vs. CC, OR = 1.30 [0.79-2.15]); the dominant model (OR = 0.80 [0.63-1.02]; and the recessive model (OR = 0.83 [0.57-1.22]). In the sensitivity analysis by ethnicity, no statistically significant associations were detected in Asians. However, in Caucasian women the T allele contrast model and the TT genotype were each associated with increased risk: T vs. C, pooled OR (95% CI) = 1.26 (1.04-1.52) and TT vs. CC, OR = 1.48 (1.04-2.11). Accordingly, the dominant model yielded statistically significant results (pooled OR = 0.71, 95% CI: 0.52-0.96) but not with the allele contrast model or the co-dominant model. There was evidence of publication bias (P = 0.02 for recessive model). In conclusion, there is limited evidence to indicate that the ABCB1 C3435T and rs2214102 G>A polymorphisms are associated with increased risk of breast cancer.

Association between polymorphisms of the ataxia telangiectasia mutated gene and breast cancer risk: evidence from the current studies.

Epidemiological studies have evaluated the association between ataxia telangiectasia mutated (ATM) gene polymorphisms and breast cancer risk. However, published data are still inconclusive. We performed a meta-analysis for the first time, based on currently available evidence, by searching PubMed, ISI Web of Knowledge, and Embase databases to derive a more precise assessment of the relationship. Following the inclusion and exclusion criteria, nine publications were included in this meta-analysis. Of these studies, one had a deviation from the Hardy-Weinberg equilibrium (HWE) at a statistical significance level of 0.01 in controls, and another two had no available data for HWE. We observed that the ATM 5557G>A polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (recessive model: odds ratio, OR = 0.67; 95% confidence interval (CI) 0.51-0.89). For the ATM IVS38-8T>C polymorphism, no significant association was found in the allele contrast, heterozygote codominant, and dominant models. There were no available data to perform this meta-analysis in the homozygote codominant and recessive models. For the ATM IVS1+19A>T polymorphism, a significant association with breast cancer risk was found in the allele contrast model (C vs. T: OR = 1.60; 95% CI 1.02-2.52). For the IVS34+60G>A polymorphism, no significant association was found in the allele contrast, codominant, dominant, and recessive models. Egger's test did not suggest any evidence of publication bias (P = 0.47 for the recessive model). In conclusion, there is limited evidence to indicate that ATM polymorphisms are associated with increased risk of breast cancer.

Association between mitogen-activated protein kinase kinase kinase 1 rs889312 polymorphism and breast cancer risk: evidence from 59,977 subjects.

Published data on the association between mitogen-activated protein kinase kinase kinase 1 (MAP3K1) gene rs889312 polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of seven eligible articles including 26,015 cases and 33,962 controls based on the search criteria were involved in this meta-analysis. We observed that the MAP3K1 rs889312 polymorphism was significantly correlated with breast cancer risk from the fixed effects model when all studies were pooled into the meta-analysis (the allele contrast model: OR 1.09, 95% CI 1.07-1.12; the homozygote codominant: OR 1.22, 95% CI 1.15-1.29; the heterozygote codominant: OR 1.07, 95% CI 1.04-1.11; the dominant model: OR 1.10, 95% CI 1.06-1.13; the recessive model: OR 1.18, 95% CI 1.12-1.25). No significant association was found in the BRCA1 mutation carriers in all genetic models. When stratified by BRCA2 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (C vs. A: OR 1.12, 95% CI 1.01-1.23; CC vs. AA: OR 1.35, 95% CI 1.06-1.71; the recessive model: OR 1.31, 95% CI 1.05-1.65). There was no evidence for significant association between MAP3K1 rs889312 polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort for all comparison models. In conclusion, this meta-analysis suggests that the MAP3K1 rs889312 C allele is a low-penetrant risk factor for developing breast cancer, and there is limited evidence to indicate that MAP3K1 rs889312 polymorphism is associated with increased risk of breast cancer in BRCA1 mutation carriers.

[Retropubic radical prostatectomy: 10 years' experience with 100 cases].

OBJECTIVE: To summarize the experience and lessons from 100 cases retropubic radical prostatectomy performed in the past 10 years. METHODS: From July 1999 to July 2009, we performed 100 cases of retropubic radical prostatectomy, of which 84 were followed up for 3 - 120 months. We analyzed their preoperative age, PSA level, amount of intraoperative blood transfusion, operation time, urinary continence, penile erectile function, stricture of the anastomotic stoma and Qmax. RESULTS: The mean age, PSA level, amount of intraoperative blood transfusion, operation time were 66.8 yr, 20.1 ng/ml, 585.7 ml and 198.9 min; the recovery rates of bladder control at 3, 6 and 12 months postoperatively were 65.5%, 81.7% and 92.4%, respectively. At 12 months after surgery, penile erection was restored in 19 cases (42.2%), anastomotic stoma stricture developed in 5 (5.9%), Qmax averaged 20.5 ml/min, biochemical recurrence was found in 13, and 1 died from prostate cancer. CONCLUSION: Retropubic radical prostatectomy is a desirable procedure for the treatment of local prostate cancer, in which ligation of the puboprostatic ligament and prostatic venous plexus before cutting off the ligament helps improve urinary continence, protection of the neurovascular bundle and collateral pudendal artery contributes to the recovery of penile erectile function, and proper connection of urethral and bladder mucosa can reduce anastomotic stoma stricture. Postoperative external-beam radiotherapy for those with T3a or local lymph node metastasis could decrease biochemical recurrence.

Associations of multiple metals with bone mineral density: A population-based study in US adults.

Epidemiologic studies focus on combined effects of multiple metals on bone mineral density (BMD) are scarce. Therefore, this study was conducted to examine associations of multiple metals exposure with BMD. Data of adults aged ≥20 years (n = 2545) from the US National Health and Nutrition Examination Survey (NHANES, 2011-2016) were collected and analyzed. Concentrations of metals were measured in blood (cadmium [Cd], lead [Pb], mercury [Hg], and manganese [Mn]) and serum (copper [Cu], selenium [Se], and zinc [Zn]) using inductively coupled plasma mass spectrometry and inductively coupled plasma dynamic reaction cell mass spectrometry, respectively. The weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to determine the joint effects of multiple metals exposure on lumbar and total BMD. The linear regression analyses showed Pb was negatively associated with BMDs. The WQS regression analyses revealed that the WQS index was inversely related to lumbar (ß = -0.022, 95% CI: -0.036, -0.008) and total BMD (ß = -0.015, 95% CI: -0.024, -0.006), and Se, Mn, and Pb were the main contributors for the combined effects. Additionally, nonlinear dose-response relationships between Pb, Mn, and Se and BMD, as well as a synergistic interaction of Pb and Mn, were found in the BKMR analyses. Our findings suggested co-exposure to Cd, Pb, Hg, Mn, Cu, Se, and Zn (above their 50th percentiles) was associated with reduced BMD, and Pb, Mn, and Se were the main contributors driving the overall effects.