CD34 Chimerism Directed Donor Lymphocyte Infusion With or Without Azacitidine Results in Reduced Relapse and Superior Overall Survival When Full Donor Chimerism is Achieved in Allogeneic Stem Cell Transplant Recipients With Acute Myeloid Leukaemia/Myelodysplastic Syndrome.

BACKGROUND: Regular monitoring of CD34 donor chimerism (DC) is a highly sensitive method of predicting relapse in allogeneic stem cell transplant (alloHSCT) recipients with AML/MDS. A fall of CD34 DC below 80% is an indicator of ensuing relapse. There are limited studies assessing the efficacy of donor lymphocyte infusion (DLI) triggered by mixed CD34 DC (MDC), in addressing falling chimerism. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive alloHSCT patients between 2012 to 2023 who received DLI (with or without azacitidine) for CD34 MDC without morphologic relapse at the time of infusion. RESULTS: Of the 21 patients with follow up CD34 DC available, 14 (66.7%) achieved CD34 full donor chimerism (FDC) following DLI with or without azacitidine (dli-FDC), while 7 (33.3%) did not (dli-MDC). The 2-year cumulative incidence of relapse (CIR) was significantly lower in dli-FDC compared to dli-MDC (21.4% vs. 85.7%, P < 0.001), correlating with superior overall survival (OS; median years not reached vs. 0.67 years [95% CI, 0.58-ND], P < .001). Rates of grade II-IV acute GVHD post-DLI were 14.9%, and moderate-severe cGVHD was 42.8% in the dli-FDC group. The 5-year nonrelapse mortality (NRM) of the dli-FDC group was 7.1% following DLI. CONCLUSION: Our study shows the restoration of CD34 FDC post-DLI is associated with reduced relapse and improved overall survival, with low NRM.

Muscle reconstruction using a five-flap method with a short straight-line incision in unilateral incomplete cleft lip repair.

When performing a unilateral incomplete cleft lip repair, it is essential to create a good sub-structure of the upper lip contour, reconstruct the orbicularis oris muscle, and prevent an unwanted scar. The aim of this study was to investigate the clinical effect of muscle reconstruction using a five-flap method with a short straight-line incision in unilateral incomplete cleft lip repair. Thirty-two infants with unilateral incomplete cleft lip were treated with this method between April 2020 and February 2023. A short straight-line incision was designed along the philtral column. The orbicularis oris muscle was reconstructed with a five-flap method in three areas: nasal base area, white lip area, and red lip area. Patient outcomes were assessed through subjective evaluation and anthropometric measurements. No patient experienced any postoperative complications. The philtral column and Cupid's bow were well reconstructed. Deviation of nasal columella was corrected and the nasal floor was elevated. Functionally and aesthetically satisfactory outcomes were obtained in all patients over long-term follow-up. In conclusion, this technique was able to create a good sub-structure of the nasolabial contour and bring a significant improvement in bilateral symmetry, showing it to be an effective method for incomplete unilateral cleft lip repair with minimal scarring.

[Clinical effects of flaps or myocutaneous flaps transplantation after titanium mesh-retaining debridement in repairing the wounds with exposed titanium mesh after cranioplasty].

Objective: To explore the clinical effects of flaps or myocutaneous flaps transplantation after debridement to repair the wounds with exposed titanium mesh after cranioplasty on the premise of retaining the titanium mesh. Methods: This study was a retrospective observational study. From February 2017 to October 2022, 22 patients with titanium mesh exposure after cranioplasty who met the inclusion criteria were admitted to the Department of Plastic, Aesthetic & Maxillofacial Surgery of the First Affiliated Hospital of Xi'an Jiaotong University, including 15 males and 7 females, aged from 19 to 68 years. After admission, treatments such as bacterial culture of wound exudate sample, anti-infection, and dressing change were carried out. Thorough surgical debridement was performed when the wound improved, and the wound area was 3.0 cm×2.0 cm to 11.0 cm×8.0 cm after debridement. The wound was repaired with local flaps, expanded flaps, or free latissimus dorsi myocutaneous flaps according to the size, location, severity of infection, and surrounding tissue condition of the wounds, and the areas of flaps or myocutaneous flaps were 5.5 cm×4.0 cm to 18.0 cm×15.0 cm. The donor areas of flaps were sutured directly or repaired by split-thickness skin grafts from head. The wound repair method was recorded. The survivals of flaps or myocutaneous flaps after surgery and wound healing in 2 weeks after surgery were recorded. During postoperative follow-up, recurrence of infection or titanium mesh exposure in the implanted area of titanium mesh was observed; the head shapes of patients, scar formation of the operative incision, and baldness were observed. At the last follow-up, the satisfaction of patients with the treatment effect (dividing into three levels: satisfied, basically satisfied, and dissatisfied) was evaluated. The total treatment costs of patients during their hospitalization were calculated. Results: The wounds in 11 cases were repaired with local flaps, the wounds in 5 cases were repaired with expanded flaps, and the wounds in 6 cases were repaired with free latissimus dorsi myocutaneous flaps. All flaps or myocutaneous flaps survived completely after surgery, and all wounds healed well in 2 weeks after surgery. Follow up for 6 to 48 months after operation, only one patient with local flap grafting experienced a recurrence of infection in the titanium mesh implanted area at more than one month after surgery, and the titanium mesh was removed because of ineffective treatment. Except for one patient who had a local depression in the head after removing the titanium mesh, the rest of the patients had a full head shape. Except for myocutaneous flap grafting areas in 6 cases and skin grafting area in 1 case with local flaps grafting had no hair growth, the other patients had no baldness. All the scars in surgical incision were concealed. At the last follow-up, 19 cases were satisfied with the treatment effects, 2 cases were basically satisfied, and 1 case was dissatisfied. The total treatment cost for patients in this group during hospitalization was 11 764-36 452 (22 304±6 955) yuan. Conclusions: For patients with titanium mesh exposure after cranioplasty, on the premise of adequate preoperative preparation and thorough debridement, the wound can be repaired with appropriate flaps or myocutaneous flaps according to the wound condition. The surgery can preserve all or part of the titanium mesh. The postoperative wound healing is good and the recurrence of infection or titanium mesh exposure in the titanium mesh implanted area is reduced, leading to good head shape, reduced surgical frequency, and decreased treatment costs.

SLCO1B3 and SLCO2B1 genotypes, androgen deprivation therapy, and prostate cancer outcomes: a prospective cohort study and meta-analysis.

Solute carrier organic anion (SLCO) transporters (OATP transporters) are involved in cellular uptake of drugs and hormones. Germline variants in SLCO1B3 and SLCO2B1 have been implicated in prostate cancer progression and therapy response, including to androgen deprivation and statin medications, but results have appeared heterogeneous. We conducted a cohort study of five single-nucleotide polymorphisms (SNPs) in SLCO1B3 and SLCO2B1 with prior evidence among 3208 men with prostate cancer who participated in the Health Professionals Follow-up Study or the Physicians' Health Study, following participants prospectively after diagnosis over 32 years (median, 14 years) for development of metastases and cancer-specific death (lethal disease, 382 events). Results were suggestive of, but not conclusive for, associations between some SNPs and lethal disease and differences by androgen deprivation and statin use. All candidate SNPs were associated with SLCO mRNA expression in tumor-adjacent prostate tissue. We also conducted a systematic review and harmonized estimates for a dose-response meta-analysis of all available data, including 9 further studies, for a total of 5598 patients and 1473 clinical events. The A allele of the exonic SNP rs12422149 (14% prevalence), which leads to lower cellular testosterone precursor uptake via SLCO2B1, was associated with lower rates of prostate cancer progression (hazard ratio per A allele, 0.80; 95% confidence interval, 0.69-0.93), with little heterogeneity between studies (I2, 0.27). Collectively, the totality of evidence suggests a strong association between inherited genetic variation in SLCO2B1 and prostate cancer prognosis, with potential clinical use in risk stratification related to androgen deprivation therapy.

[Clinical effects of free pre-expanded internal thoracic artery perforator pedicled deltopectoral flap transfer in facial scar reconstruction].

Objective: To explore the clinical effects of free pre-expanded deltopectoral flap transfer in facial scar reconstruction by selecting appropriate internal thoracic artery perforator as the pedicle through preoperative color Doppler ultrasonic vascular assessment. Methods: A retrospective observational study was conducted. From September 2017 to March 2021, 11 patients with facial scar who met the inclusion criteria were admitted to the First Affiliated Hospital of Xi'an Jiaotong University, including 6 males and 5 females, aged 16-58 (31±12) years. The scar with area ranging from 7 cm×5 cm to 14 cm×9 cm was reconstructed by free pre-expanded internal thoracic artery perforator pedicled deltopectoral flap transfer. The operation was performed in 2 or 3 stages. Before operation, color Doppler ultrasonography was performed to evaluate the internal thoracic artery perforator. In the first stage, skin and soft tissue expander (hereinafter referred to as expander) implantation was performed, and a cylindrical expander with rated capacity of 400 to 600 mL was placed in the chest wall. The expansion time was 3 to 4 months, and the water injection volume reached 1.2-1.5 times of the rated capacity of expander. In the second stage, scar excision+free pre-expanded deltopectoral flap transfer was performed, with harvested flap area ranging from 9 cm×7 cm to 16 cm×10 cm. The vascular pedicle of flap (intercostal perforator of internal thoracic artery) was anastomosed end-to-end to the facial artery and vein or superficial temporal artery and vein. The wound in donor site was closed directly. Third stage operation thinning was performed at 3-6 months after the second stage operation in 5 patients because of bloated flap pedicle. At 6 months after the last operation, the flap survival and complications were recorded, the sensation of flap was evaluated by Semmes-Weinstein monofilament test, the color of flap was evaluated by color contrast of the flap to surrounding normal skin, and the curative effect satisfaction degree of patients was evaluated by 5-grade Likert scale. Results: At 6 months after the last operation, all the flaps of 11 patients survived well. One patient experienced venous congestion after flap transplantation, but the flap survived after re-anastomosis. One patient experienced hematoma after the first stage operation of expander implantation, but the rest treatment was not influenced after hematoma removal. No complications such as infection or expander exposure occurred in any patient. At 6 months after the last operation, the sensation of flap of patient was as follows: 9 cases recovered to protective sensation decrease or better, 1 case had protective sensation defect, and 1 case only had deep touch and pressure sensation; the color of flap of patient was as follows: 3 cases were very close to the color of surrounding normal skin, 6 cases were close to the color of surrounding normal skin, and 2 cases were different to the color of surrounding normal skin; the curative effect satisfaction degree of patients was as follows: 2 patients were very satisfied, 6 patients were satisfied, 2 patients were somewhat satisfied, and 1 patient was a little not satisfied. Conclusions: The large area facial scar can be treated safely and effectively by free pre-expanded deltopectoral flap with appropriate single internal thoracic artery perforator as vascular pedicle selected through vascular assessment by color Doppler ultrasonography before operation. After operation, the color of flap of patients is close to the surrounding normal skin and the sensation of flap can be partially recovered, with high curative effect satisfaction degree of patients.

[Resistance to deltamethrin and its association with mutation sites in the sodium iron channel domain III gene in Rhipicephalus microplus in Huaihua City of Hunan Province].

OBJECTIVE: To investigate the level of deltamethrin resistance and mutation sites in the sodium iron channel gene in Rhipicephalus microplus in Huaihua City, Hunan Province, and to examine the correlation between deltamethrin resistance and mutation sites in the sodium iron channel gene in Rh. microplus. METHODS: Rh. microplus was sampled from multiple yellow cattle farms in Huaihua City, Hunan Province from June to September 2022, and the level of resistance to deltamethrin was determined in ticks using the adult immersion test. The sodium iron channel domain III gene was amplified in deltamethrin-resistant and wild-type Rh. microplus using PCR assay. Following sequencing and sequence alignment, mutation sites were detected in bases. The sodium iron channel domain III gene in Rh. microplus was translated, and the signal peptide, transmembrane domain, and phosphorylation and glycosylation sites were detected in amino acid sequences. The tertiary structures of the sodium iron channel domain III protein of deltamethrin-resistant and wild-type Rh. microplus were deduced and compared, and the association be tween mutation sites in bases and resistance to deltamethrin was examined in Rh. microplus according the level of deltamethrin resistance, sequence alignment and protein tertiary structure. RESULTS: The median (LC50) and 95% lethal concentrations (LC95) of deltamethrin were 121.39 mg/L and 952.61 mg/L against Rh. microplus, with a resistance factor of 9.24 and level II resistance. The sequence of the sodium ion channel domain III gene was 1 010 bp in size, and mutation sites were detected in two neighboring bases in the sequence of the sodium ion channel domain III gene in deltamethrin-resistant Rh. microplus. Although no signal peptides were found in the sodium iron channel domain III protein of deltamethrin-resistant or wild-type Rh. microplus, 6 trans-membrane domains, 42 phosphorylation sites and 8 glycosylation sites were identified, with a significant difference in the tertiary structure of the sodium iron channel domain III protein between deltamethrin-resistant and wild-type Rh. microplus. CONCLUSIONS: Level II resistance to deltamethrin is detected in Rh. microplus in Huaihua City, Hunan Province, and two mutation sites that correlate with the emergence of deltamethrin resistance are identified in the sequence of the sodium iron channel domain III gene in deltamethrin-resistant Rh. microplus.

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

The Ponseti Method Decreased the Surgical Incidence in Children with Congenital Clubfoot: A Population-Based, 8 Birth-Year Cohort Study.

BACKGROUND: With the introduction of the Ponseti method for congenital clubfoot, the relapse rate and the surgical rate have been remarkably reduced. However, data from population studies for patients up to 10 years of age are still lacking. This study aimed to survey the relapse and surgery rates in the first 10 years of life in children with congenital clubfoot before and after introduction of the Ponseti method in Taiwan using the National Health Insurance Research Database (NHIRD). METHODS: We retrieved clubfoot cases and related surgical procedures determined by International Classification of Diseases, Ninth Revision (ICD-9) 754.51 from the 1999-2016 NHIRD. Foot and ankle surgical procedures coded as ICD-9 754.51 for patients who were older than 6 months of age were regarded as surgical procedures for relapsed or residual deformities. The rate of clubfoot release when the patients were 0.5 to 1 year of age and extensive surgical procedures in the first 10 years of life were assessed among 8 birth-year cohorts (1999 to 2006) with a 10-year follow-up. RESULTS: Among 622 children with idiopathic congenital clubfoot diagnosis, 301 underwent a total of 367 surgical procedures for clubfoot between 6 months and 10 years of age. Disease incidence of 0.32 per 1,000 live births remained stable in the 8 birth-year cohorts. After the Ponseti method was introduced in 2002, there was a decrease in the clubfoot release rate in the 0.5 to 1-year age group (25.8% in the 1999 to 2002 birth-year cohorts compared with 17.6% in the 2003 to 2006 birth-year cohorts) and the rate of extensive surgical procedures (41.5% in the 1999 to 2002 birth-year cohorts compared with 31.3% in the 2003 to 2006 birth-year cohorts), both determined to be significant at p < 0.05 using the chi-square test. A significant decreasing trend (p < 0.05) was revealed in the rate of clubfoot release in patients who were 0.5 to 1 year of age by polynomial correlation, with an increasing negative slope after a turning point around 2002. The Ponseti method increased the ratio of minor to extensive surgical procedures when a surgical procedure was required. CONCLUSIONS: The Ponseti method decreased subsequent extensive surgical procedures for clubfoot, especially in the group that was 0.5 to 1 year of age. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Real-world study on clinical outcomes of nucleos(t)ide analogues antiviral therapy in patients with chronic hepatitis B.

Nucleos(t)ide analogues (NAs) are widely used for antiviral therapy in patients with chronic hepatitis B (CHB), but real-world data on treatment patterns and long-term clinical outcomes are not always available. Using data from electronic medical records between January 2011 and December 2016 in Shanghai, China, we evaluated patient characteristics, treatment patterns and clinical outcomes in patients with CHB. There were 6688 patients in the study cohort. The incidences of cirrhosis and hepatocellular carcinoma (HCC) were 41.0‰ and 6.8‰ person-years, respectively. There were more cirrhosis and HCC cases among patients who had shorter NA treatment duration (<365 days), or who were less compliant (<80%). In addition, increased risk of cirrhosis and HCC was observed in patients who did not achieve hepatitis B surface antigen (HBsAg) loss/seroconversion. Moreover, patients with cirrhosis developed after antiviral treatments had a higher incidence of HCC (adjusted hazard ratio 15.86, 95% confidence interval 7.35-34.24). Good compliance with treatment and longer treatment duration significantly decreased the risk of developing cirrhosis and HCC. HBsAg loss seemed to be a protective factor for cirrhosis/HCC in NAs-treated patients with CHB, and cirrhosis was a confirmed risk factor for HCC development as expected.

Association of genetic variation of the six gene prognostic model for castration-resistant prostate cancer with survival.

BACKGROUND: We previously identified a blood RNA transcript-based model consisting of six immune or inflammatory response genes (ABL2, SEMA4D, ITGAL, C1QA, TIMP1, and CDKN1A) that was prognostic for survival in cohorts of men with castration-resistant prostate cancer (CRPC). We investigated whether inherited variation in these six genes was associated with overall survival (OS) in men with CRPC. METHODS: The test cohort comprised 600 patients diagnosed with CRPC between 1996 and 2011 at Dana-Farber Cancer Institute. Genotyping of 66 tagging single nucleotide polymorphisms (SNPs) spanning the six genes was performed on blood derived DNAs. For the top four SNPs (P < 0.05), validation was conducted in an independent cohort of 223 men diagnosed with CRPC between 2000 and 2014. Multivariable Cox regression adjusting for known prognostic factors estimated hazard ratios (HR) and 95% confidence intervals (CI) of the association of genetic variants with OS. RESULTS: Two thirds of patients in both cohorts had metastases at CRPC diagnosis. Median OS from CRPC diagnosis was 3.6 (95%CI 3.3-4.0) years in the test cohort and 4.6 (95%CI 3.8-5.2) years in the validation cohort. Fifty-nine SNPs in Hardy-Weinberg equilibrium were analyzed. The major alleles of rs1318056 and rs1490311 in ABL2, and the minor alleles of rs2073917 and rs3764322 in ITGAL were associated with increased risk of death in the test cohort (adjusted-HRs 1.27-1.39; adjusted-p <0.05; false discovery rate <0.35). In the validation cohort, a similar association with OS was observed for rs1318056 in ABL2 (adjusted-HR 1.44; 95%CI 0.89-2.34) and rs2073917 in ITGAL (adjusted-HR 1.41; 95%CI 0.82-2.42). The associations did not reach statistical significance most likely due to the small sample size of the validation cohort (adjusted-p = 0.142 and 0.209, respectively). Additional eQTL analysis indicated that minor alleles of rs1318056 and rs1490311 in ABL2 are associated with a lower ABL2 expression in blood. CONCLUSIONS: These findings corroborate our initial work on the RNA expression of genes involved in immunity and inflammation from blood and clinical outcome and suggest that germline polymorphisms in ABL2 and ITGAL may be associated with the risk of death in men with CRPC. Further studies are needed to validate these findings and to explore their functional mechanisms.

[The effect and comparison of commonly used liver-protection drugs for irradiated HL-7702 by X].

Objective: To investigate the effect of different mechanisms of liver-protection drugs in clinic and compare which one is best for the proliferation of irradiated HL-7702, laying the basis of liver-protection drugs choose in clinic on theory and practice. Methods: Human liver parenchyma cells HL-7702 were given single 6 MV X ray irradiation at a dose of 10Gy, the cells' morphology were detected under an inverted microscope at 24h, 48h and 72h. Then, MTT was used to assess the survival rate of the cells to evaluate the effect of the X ray. The representive medicines which mechanism may relate to RILD were chosen and diluted into various concentrations with culture medium according to clinical and relative reports. Different concentrations of medicines were used to protect the cells damaged by the X ray. Comparing the effect with MTT and measure SOD, MDA for the best one. Further research on its protection of oxidative damage. T-test, F test and non- paramiter test were used for statistical analysis. Results: 2.5 mg/ml and 1 mg/ml of magnesium isoglycyrrhizinate both have an effect on the proliferation of liver cells, especially the concentration of 1 mg/ml. The injection of polyene phosphatidyl choline show trivial effect at the concentrations of 250 µmol/L and reduced glutathione(GSH) did not demonstrate relative functions. Further research on the magnesium isoglycyrrhizinate, found its protection at 48h to oxidative damage (P < 0.05), but the effect is weak at 24h and 48h. Conclusions: In three kinds of representing medicines, magnesium isoglycyrrhizinate has preferable effects on liver parenchyma cells and show a bright future in the treatment of RILD.

Comparison of laparoscopy and open surgery in treating severe acute pancreatitis and its relative aftercare.

This study was designed to determine the effects and compare laparoscopic intervention and open surgery in treating severe acute pancreatitis (SAP) and its relative aftercare, to improve the overall treatment of SAP. Ninety patients with SAP were enrolled from the 2nd Affiliated Hospital of Harbin Medical University from 2008 to 2014 and divided into a laparoscopic intervention group (25 cases) and an open surgery group (65 cases). Patients were asked for clinical symptoms, general hospital information, laboratory inspection, imageological examination, local and systemic complications, treatment and outcome. SAP patients’ relevant clinical indicators were compared between the two groups before and after the operation. Results revealed that there was no statistical significance in lesion range and main scoring indexes for reflecting the severity of the disease. For both groups statistical significance was found in blood loss (285.3±79.8 mL vs 362±91.6 mL), intensive care unit (ICU) monitoring time (9.04±6.35 d vs 12.48±8.34 d) and service time of breathing machine (9.47±6.24 d vs 12.98±8.25 d), and the laparoscopic operation group was superior to the open surgery group (p < 0.05). Besides, the laparoscopic operation group was also superior to the open surgery group in demand for main analgesics one week after the operation, as well as for recovery rate and incidence of complications (p < 0.05). Thus, it can be concluded that patients undergoing laparoscopic intervention are less likely to develop pulmonary infection and more likely to be cured in comparison with patients who receive open surgery. In addition, laparoscopic intervention results in less damage, lighter pain and fewer complications compared with open surgery.

The incidence of tympanogenic labyrinthitis ossificans.

OBJECTIVE: To estimate the incidence of tympanogenic labyrinthitis ossificans. METHODS: The records of patients treated with mastoidectomy for various tympanogenic aetiologies from January 2007 to December 2011 were retrospectively reviewed. Patients whose high-resolution computed tomography scans showed evidence of labyrinthine calcification of the temporal bone were enrolled. Patients with a history of head and neck cancer, meningitis, and otosclerosis, and patients with cochlear implants, were excluded from this study. RESULTS: A total of 195 patients were enrolled in this study; 4 of the patients presented with calcification in the inner ear. Therefore, the incidence of tympanogenic labyrinthitis ossification was 2 per cent. The computed tomography findings revealed: (1) cochlear calcifications of the basal and middle turn in two patients; and (2) vestibular, superior semicircular canal, posterior semicircular canal and lateral semicircular canal calcification in one, four, three and two patients, respectively. CONCLUSION: The incidence of tympanogenic labyrinthitis ossification in patients who had undergone a mastoidectomy was 2 per cent.

Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer.

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits.

Ample evidence supports genetic and functional heterogeneity in primary tumors, but it remains unclear whether circulating tumor cells (CTCs) also exhibit the same hierarchical organization. We examined the functional diversity of viable, single CTCs using an array of subnanoliter wells (nanowells). The compartmentalization of single cells by nanowells allowed clonal comparison and mapping of heterogeneity of single cells or preformed clusters of cells. By measuring the short-term viability, invasiveness and secretory profiles of individual CTCs, it was evident that only a rare subset of CTCs possessed malignant traits indicative of metastatic potential in late-stage, progressing metastatic castration-resistant prostate cancer (mCRPC) patients. These CTCs were resistant to anoikis after being in the circulation, were invasive in their epithelial state, or secreted proteases capable of cleaving peptide substrates. Every CTC observed, however, did not exhibit such metastatic potential, suggesting that enumeration of CTCs alone may be insufficient to understand metastasis or stratify patients.

KLRG1 impairs CD4+ T cell responses via p16ink4a and p27kip1 pathways: role in hepatitis B vaccine failure in individuals with hepatitis C virus infection.

Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4(+) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4(+) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4(+) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4(+) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4(+) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.

Porphyrin metabolisms in human skin commensal Propionibacterium acnes bacteria: potential application to monitor human radiation risk.

Propionibacterium acnes (P. acnes), a Gram-positive anaerobic bacterium, is a commensal organism in human skin. Like human cells, the bacteria produce porphyrins, which exhibit fluorescence properties and make bacteria visible with a Wood's lamp. In this review, we compare the porphyrin biosynthesis in humans and P. acnes. Also, since P. acnes living on the surface of skin receive the same radiation exposure as humans, we envision that the changes in porphyrin profiles (the absorption spectra and/or metabolism) of P. acnes by radiation may mirror the response of human cells to radiation. The porphyrin profiles of P. acnes may be a more accurate reflection of radiation risk to the patient than other biodosimeters/biomarkers such as gene up-/down-regulation, which may be non-specific due to patient related factors such as autoimmune diseases. Lastly, we discuss the challenges and possible solutions for using the P. acnes response to predict the radiation risk.

Elevated expressions of p53, CDKNA1, and Bax in placental villi from patients with recurrent spontaneous abortion.

OBJECTIVE: This study assessed the relationship between the p53-dependent apoptosis and recurrent spontaneous abortion (RSA). PATIENTS AND METHODS: Thirty women with recurring miscarriages were enrolled as experimental group, and 30 women with normal reproduction served as control group. Immunohistochemistry was used to evaluate expression of p53 in villous tissue specimens. Further, expressions of CDKN1A and Bax mRNAs were evaluated by qPCR. TUNEL assay was utilized to document cell apoptosis. RESULTS: Expression of p53 was significantly increased in chorionic villi of patients in experimental group (p < 0.05 vs. control group). Further, CDKN1A and Bax mRNA levels were elevated in experimental group (p < 0.05 vs. control group), and the cell apoptosis index was increased as well. CONCLUSIONS: The p53-CDKN1A and p53-Bax signaling pathways appear to be activated in RSA. Thus, the apoptosis pathways controlled by p.

MiR-135a functions as a selective killer of malignant glioma.

Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malignant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy.

Sizes and polycyclic aromatic hydrocarbon composition distributions of nano, ultrafine, fine, and coarse particulates emitted from a four-stroke motorcycle.

Thus, this study was undertaken to determine the size distribution, concentration, species, and carcinogenic potency of particulate matter and particle-bound polycyclic aromatic hydrocarbons (PAHs) emitted from 4-st/mc at various speeds (idle, 15 km/h, 30 km/h). Approximately 80% of the particles emitted from the that is, they are primary inhalable particulates. The particle total number concentrations (TNCs) emitted while idling and at 15 and 30 km/h were 2.07 x 104, 2.35 x 104, and 2.60 x 104 #/cm³, respectively; i.e., they increased at elevated speeds. Notably, most of the particles emitted at 30 km/h had diameters of less than 0.65 µm and contained higher percentages of total PAHs. Excluding incomplete combustion, we suspected that some of the lower-molecular-weight PAHs [phenanthrene (PA), anthracene (Ant), pyrene (Pyr)] obtained in the fine particles at idle originated from unburned 95-octane unleaded fuel. When operated at 15 km/h, pyrolysis of the PAHs dominated, resulting in increased amounts of medium-molecular-weight PAHs {fluorene (FL), Pyr, benz[a]anthracene (BaA), chrysene (CHR)} in the ultrafine particles. Furthermore, at 30 km/h, more pyrosynthesis products {benzo[a]pyrene (BaP), indeno[1,2,3,-cd]pyrene (IND), dibenz[a,h]anthracene (DBA)}, induced through combustion at the correspondingly higher temperature, were exhausted with the nanoparticles. Although the total concentrations of BaP-equivalent emissions were inconsistent with the total PAHs, the nanoscale-sized particulates emitted from the 4-st/mc at higher speeds had the strongest PAH-related carcinogenic potencies, which should be a great concern.