High-risk Types Research Articles

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

A microfluidic-chip-based system with loop-mediated isothermal amplification for rapid and parallel detection of Trichomonas vaginalis and human papillomavirus.

Cervical cancer is a significant global health issue primarily caused by high-risk types of human papillomavirus (HPV). Recent studies have reported an association between Trichomonas vaginalis (T. vaginalis) infections and HPV infections, highlighting the importance of simultaneously detecting these pathogens for effective cervical cancer risk management. However, current methods for detecting both T. vaginalis and HPV are limited. In this study, we present a novel approach using a microfluidic-chip-based system with loop-mediated isothermal amplification (LAMP) for the rapid and parallel detection of T. vaginalis, HPV16, HPV18, and HPV52 in a reagent-efficient and user-friendly manner. Compared to conventional LAMP assays in tubes, our system exhibits enhanced sensitivity with values of 2.43 × 101, 3.00 × 102, 3.57 × 101, and 3.60 × 102 copies per reaction for T. vaginalis, HPV16, HPV18, and HPV52, respectively. Additionally, we validated the performance of our chip by testing 47 clinical samples, yielding results consistent with the diagnostic methods used by the hospital. Therefore, our system not only offers a promising solution for concurrent diagnosis of T. vaginalis and HPV infections, particularly in resource-limited areas, due to its cost-effectiveness, ease of use, and rapid and accurate detection performance, but can also contribute to future research on the co-infection of these two pathogens. Moreover, the system possesses the capability to simultaneously detect up to 22 different types of pathogens, making it applicable across a wide range of domains such as diagnostics, food safety, and water monitoring.

Perianal fistulizing Crohn's disease is associated with a higher prevalence of HPV in the anorectal fistula tract. A comparative study

Background & AimsPerianal fistulizing Crohn's disease is the main risk factor for anal cancer in patients with inflammatory bowel disease. Whether this occurs due to a higher frequency of human papillomavirus remains unclear. The authors aimed to evaluate the prevalence of HPV and high-risk HPV in patients with perianal Crohn's disease, compared with a control group. MethodsThe authors conducted a two-center cross-sectional study in which perianal fistulizing Crohn's disease patients were matched for age and sex with patients with anorectal fistula without Crohn's disease. Biopsy specimens were obtained from fistulous tracts during examination under anesthesia for both groups. The samples were sent for HPV detection and genotyping using the INNO-LiPA test. ResultsA total of 108 subjects (54 in each group) were recruited. The perianal fistulizing Crohn's disease group showed a statistically higher frequency of HPV in the fistulous tract than the control group (33.3% vs. 16.7%; p = 0.046). Separate analyses on high-risk types demonstrated that there was a numerically higher frequency of HPV in the perianal fistulizing Crohn's disease group. In multiple logistic regression, patients with perianal fistulizing Crohn's disease were found to have a chance of HPV 3.29 times higher than patients without Crohn's disease (OR = 3.29; 95% CI 1.20‒9.01), regardless of other variables. The types most frequently identified in the perianal fistulizing Crohn's disease group were HPV 11 (12.96%) and HPV 16 (9.26%). ConclusionPerianal fistulizing Crohn's disease is associated with a higher prevalence of HPV than in patients with anorectal fistula without Crohn's disease.

AuPt nanoalloy with dual functionalities for sensitive detection of HPV16 DNA.

Human papillomavirus type 16 (HPV16), one of the high-risk types, is responsible for 53% of cervical cancers. The development of an early diagnostic approach with high sensitivity, low-cost, point-of-care testing (POCT) for HPV16 is urgent. In our work, a novel dual-functional AuPt nanoalloy-based lateral flow nucleic acid biosensor (AuPt nanoalloy-based LFNAB) was established with excellent sensitivity for detecting HPV16 DNA for the first time. The AuPt nanoalloy particles were prepared by a one-step reduction method, which was simple, rapid, and green. The AuPt nanoalloy particles retained the performance of initial Au nanoparticles owing to the catalytic activity enabled by Pt. Such dual-functionalities offered two kinds of detection alternatives (i.e., normal mode and amplification mode, respectively). The former is produced just by the black color from the AuPt nanoalloy material itself, and the latter is more color sensitive from its superior catalytic activity. The optimized AuPt nanoalloy-based LFNAB exhibited satisfactory quantitative ability in detecting the target HPV16 DNA in the range of 5-200 pM with a LOD of 0.8 pM at the "amplification mode". The proposed dual-functional AuPt nanoalloy-based LFNAB displayed great potential and promising opportunity in POCT clinical diagnostics.

Poly(I:C) Treatment Prevents Skin Tumor Formation in the Preclinical HPV8 Transgenic Mouse Model

Actinic keratoses and cutaneous squamous cell carcinomas are associated with infections with human papillomavirus of genus beta (betaHPV) in immunosuppressed patients. To date, targeted therapy against betaHPV-associated skin cancer does not exist because of the large number of betaHPV without defined high-risk types. In this study, we hypothesized that the activation of innate antiviral immunity in the skin, asymptomatically infected with betaHPV, induces an antitumor response by in situ autovaccination and prevents the formation of betaHPV-associated skin cancer. To test this, we used the preclinical keratin-14-HPV8 transgenic mouse model, which develops skin tumors after mechanical wounding. Remarkably, treatment with the antiviral immune response activating polyinosinic-polycytidylic acid (poly[I:C]) completely prevented cutaneous tumor growth. The induction of the IFN-induced genes Cxcl10 and Ifit1 by poly(I:C) depended on MDA5 activation. Increased numbers of total and activated CD4 and CD8 T cells were detected in poly(I:C)-treated skin. T cells were found in the skin of poly(I:C)-treated mice but not in the skin tumors of untreated mice. T-cell depletion showed a predominant role of CD4 T cells in poly(I:C)-mediated tumor prevention. Our findings identify the MDA5 ligand poly(I:C) as a promising candidate for in situ autovaccination approaches, which might serve as a treatment strategy against betaHPV-related skin diseases.

Ring finger protein 126 promotes breast cancer metastasis and serves as a potential target to improve the therapeutic sensitivity of ATR inhibitors

Background/aimsThis study explores the relationship between the E3 ubiquitin ligase Ring finger protein 126 (RNF126) and early breast cancer metastasis and tests the hypothesis that RNF126 determines the efficacy of inhibitors targeting Ataxia telangiectasia mutated and Rad3-related kinase (ATR).MethodsVarious metastasis-related genes were identified by univariable Cox proportional hazards regression analysis based on the GSE11121 dataset. The RNF126-related network modules were identified by WGCNA, whereas cell viability, invasion, and migration assays were performed to evaluate the biological characteristics of breast cancer cells with or without RNF126 knockdown. MTT, immunoblotting, immunofluorescence, and DNA fiber assays were conducted to determine the efficiency of ATR inhibitor in cells with or without RNF126 knockdown.ResultsRNF126 was associated with early breast cancer metastasis. RNF126 promoted breast cancer cell proliferation, growth, migration, and invasion. ATR inhibitors were more effective at killing breast cancer cells with intact RNF126 due to replication stress compared with the corresponding cells with RNF126 knockdown. Cyclin-dependent kinase 2 (CDK2) was involved in regulating replication stress in breast cancer cells with intact RNF126.ConclusionA high level of expression of RNF126 in early breast cancer patients without lymph node metastases may indicate a high-risk type of metastatic disease, possibly due to RNF126, which may increase breast cancer cell proliferation and invasion. RNF126-expressing breast cancer cells exhibit CDK2-mediated replication stress that makes them potential targets for ATR inhibitors.

Characterization of Human Papillomavirus 16 from Kinshasa (Democratic Republic of the Congo)-Implications for Pathogenicity and Vaccine Effectiveness.

Human Papillomavirus (HPV) type 16 is the main etiological agent of cervical cancer worldwide. Mutations within the virus genome may lead to an increased risk of cancer development and decreased vaccine response, but there is a lack of information about strains circulating in Sub-Saharan Africa. Endocervical cytology samples were collected from 480 women attending a voluntary cervical cancer screening program at Monkole Hospital and four outpatient centers in Kinshasa, Democratic Republic of the Congo (DRC). The prevalence of HPV infection was 18.8% and the most prevalent high-risk types were HPV16 (12.2%) followed by HPV52 (8.8%) and HPV33/HPV35 (7.8% each). HPV16 strains were characterized: 57.1% were classified as C lineage; two samples (28.6%) as A1 and one sample belonged to B1 lineage. HPV33, HPV35, HPV16, and HPV58 were the most frequent types associated with low-grade intraepithelial lesion while high-grade squamous intraepithelial lesions were predominantly associated with HPV16. Several L1 mutations (T266A, S282P, T353P, and N181T) were common in Kinshasa, and their potential effect on vaccine-induced neutralization, especially the presence of S282P, should be further investigated. Long control region (LCR) variability was high with frequent mutations like G7193T, G7521A, and G145T that could promote malignancy of these HPV16 strains. This study provides a helpful basis for understanding HPV16 variants circulating in Kinshasa and the potential association between mutations of LCR region and malignancy and of L1 and vaccine activity.

Correlation Between E6 and E7 Oncogene Mutation Human Papilloma Virus High Risk Type 16 with Retinoblastoma Protein Expression in Cervical Cancer

Introduction: The E6 and E7 oncoproteins of high-risk Human Papillomavirus (HPV) have crucial roles in cervical cancer pathogenesis by inhibiting p53 and retinoblastoma protein (pRb) which are tumor suppressor genes. Genetic sequence mutations of E6 and E7 oncogenes can affect E6/E7 protein functions that will change E7-pRB interaction. Furthermore, this condition will influence progression cervical cancer progression in several intratypic variants of high-risk HPV type 16. Methods: A cross-sectional study was conducted from September 2020-September 2021, at the Obstetrics and Gynecology Outpatient Clinic, Prof Dr I. G. N. G. Ngoerah General Hospital. Consecutive sampling was taken by collecting cervical cancer tissue followed by isolation, amplification, and gene sequencing to assess E6 and E7 mutations. The expression of pRb was measured by immunohistochemical staining (IHC). Results: From 100 cervical cancer subjects, 31 subjects were found HPV16 positive (19 wildtype and 12 mutants). The proportion of E6 and E7 mutants was 25.8% and 12.9% respectively. This study shows that T27C/F9F; A360G/E120E and G371A/R124K variants were found on E6 oncogene mutations, meanwhile, A86C/N29T; A86G/N29S; C229T/R77C and T285C/S95S variants were detected on E7 oncogene mutations. The types of E6 mutations were T27C (16.1%), A360G (6.4%) and G371A (1 subject; 3.2%). In addition, pRb expression was stronger in mutant group than wild-type group 60.5% vs. 53%. There was no correlation between retinoblastoma protein expression and mutations E6/E7 oncogene HPV Type 16 (PR 0.22; 95% CI 0.03-1.6; p value 0.10). Conclusions: In cervical cancer, there is no significant difference between the expression of retinoblastoma protein in mutant vs wildtype E6 and E7 oncogene HPV16.

TRICIN: A Phase II Trial on the Efficacy of Topical TRIchloroacetic Acid in Patients with Cervical Intraepithelial Neoplasia.

Data on non-surgical treatment approaching persistent cervical intraepithelial neoplasia (CIN) are scarce. Retrospective analysis suggest high efficacy of topical treatment with trichloroacetic acid (TCA). This prospective phase II study set out to investigate the efficacy of a single application of 85% TCA in the treatment of CIN I/II. Patients with CIN I/II were treated a single time with 85% TCA. After three and six months colposcopic, histologic, and HPV evaluation was performed. The primary endpoint was treatment efficacy defined as complete histologic remission six months after treatment. The secondary endpoint was HPV clearance six months after treatment. A total of 102 patients with CIN I/II were included into this trial. Complete histologic remission rates were 75.5% and 78.4% three and six months after TCA treatment, respectively. Clearance rates of HPV 16, 18 and other high risk types were 76.5%, 91.7%, 68.7% after six months, respectively. Side effects of TCA were mild and lasted usually less than 30 min. This is the first prospective trial reporting high histologic complete remission rates in patients with CIN I/II after a single 85% TCA treatment. In the future, TCA may represent an effective and feasible non-surgical treatment approach for CIN.

MiR-375 Combined with SHOX2 Methylation has Higher Diagnostic Efficacy for Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) is a high-risk type of lung cancer. This study aims to improve the diagnostic efficacy of NSCLC through the combined detection of miR-375 and short-stature homeobox 2 (SHOX2) methylation. Patients with NSCLC (n = 121) and benign lung disease (BLD) (n = 121) were included. miR-375 and SHOX2 methylation levels were detected. The correlations between miR-375, SHOX2 methylation, and clinical characteristics of NSCLC were analyzed. The diagnostic efficacy of miR-375, SHOX2 methylation, and their combined detection was analyzed. The risk factors of NSCLC were analyzed. The results showed that levels of miR-375 and SHOX2 methylation in NSCLC patients were higher than those in BLD. High expression of miR-375 and positive SHOX2 methylation indicated worse pathological features of NSCLC patients. miR-375 combined with SHOX2 methylation had higher diagnostic efficacy than the single diagnosis. miR-375, SHOX2 methylation, smoking history, neuron-specific enolase (NSE), and CYFRA21-1 levels were risk factors for NSCLC; the risk of NSCLC increased 25.763 times for each unit increase in plasma miR-375 level (OR = 25.763, CI: 1.726-384.529), and the risk of NSCLC increased 4.096 times for each unit increase in SHOX2 methylation (OR = 4.096, CI: 1.195-14.036). miR-375 targeted SHOX2. Overall, miR-375 and SHOX2 methylation and their combined detection were expected to be biomarkers for the diagnosis of NSCLC.

Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity.

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.

Susceptibility of Male who Have Sex with Male to High-Risk Type Human Papillomavirus (HPV) 16 and 18 with Condyloma Acuminata

Background: Condyloma acuminatum (CA) or genital warts are sexually transmitted infections caused by human papillomavirus (HPV). It is estimated that CA occurs in >80% of reproductive age in many countries, with the most common subtypes being 6 and 11. Purpose: The aim of the study to reveal the high risk (HR)-HPV in various condyloma acuminata in Dr. Moewardi Hospital. Methods: This study was a cross-sectional analytical observational study that assessed data collection concurrently over time. Specimens were patients diagnosed with condyloma acuminatum, biopsies were performed, and immunohistochemical staining was also performed. The sampling technique used sequential sampling, and the inclusion criteria included patients who came to our hospital for treatment. Results: The majority of the male sample was MSM. According to HIV status, 6 (30%) male patients were found to be positive. Immunohistochemistry showed that 15% of the samples were HR-HPV. Statistical test results for HR-HPV and low-risk (LR) HPV were significant, p-value = 0.038. Conclusion: Condyloma acuminatum is a sexually transmitted infection that usually occurs at the same time as HIV infection. In our study all patients with HR-HPV were MSM.

Epidemiological study of HPV infection in 40,693 women in Putian: a population study based on screening for high-risk HPV infection

BackgroundThe infection rate of human papillomavirus (HPV) is high in the coastal regions of China. However, the infection rate among high-risk genotypes of women in Putian City is unknown. Therefore, this study aimed to analyse the epidemiology of high-risk HPV infection among women in Putian and provide a reference for the diagnosis, treatment and vaccination of cervical cancer in this region.MethodsThe data used were obtained from the Chinese government’s public health program (“Cervical and Breast Cancer Screening Project”). A total of 40,693 female cervical cell exfoliation samples screened for high-risk HPV at the Affiliated Hospital of Putian University from July 2020 to December 2021 were enrolled. DNA was extracted using a fully automatic extractor. Then, 14 high-risk genotypes of HPV were detected by polymerase chain reaction. The characteristics of HPV infection, distribution of high-risk genotypes, infection types and thinprep cytologic test (TCT) classification at different age groups were analysed.ResultsAmong the 40,693 samples, 3899 were infected with HPV, with an infection rate of 9.6%. Accordingly, HPV infection rates gradually increased with age, and statistically significant differences were observed among age groups (χ2 = 74.03, P < 0.01). The infection rates of high-risk HPV52, HPV58 and HPV16 were in the top three and increased with age. Single infection was dominant (84.7%), followed by double infections (12.7%). The cervical cytology of 3899 HPV-positive people can be classified into negative for intraepithelial lesion and malignancy (NILM, 88.0%), atypical squamous cells of undetermined significance (ASC-US, 6.6%), atypical squamous cells—cannot exclude high-grade squamous intraepithelial lesion (ASC-H, 1.4%), low-grade squamous intraepithelial lesion (LSIL, 3.2%) and high-grade squamous intraepithelial lesion (HSIL, 0.8%). HPV16 infection rate increased with increasing severity of cervical cytology (χ2trend = 43.64, P < 0.01), whereas the infection rates of HPV52 (χ2trend = 13.89, P < 0.01) and HPV58 (χ2trend = 13.50, P < 0.01) showed opposite trends.ConclusionThe infection rate of female HPV high-risk screening in this region was 9.6% and mainly involved single infections. In addition, HPV16, HPV52 and HPV58 were closely related to the severity of cervical cytology. Effective screening, vaccination and education are needed. The 9-valent vaccine will be effective in reducing cervical pre-invasive disease. It would also be reasonable to state that the rising trend in HPV infection and high grade cytology with age emphasises the need to target older women with screening. Vaccination of younger women (aged ≤ 25) will lay the foundation for better cancer outcomes in the future.

Bilateral information disclosure in adverse selection markets with nonexclusive competition

We study insurance markets with nonexclusive contracts, introducing bilateral endogenous information disclosure about insurance sales and purchases by firms and consumers. We show that a competitive equilibrium exists under remarkably mild conditions and characterize the unique equilibrium allocation. With two types of consumers the allocation consists of a pooling contract that maximizes the well-being of the low-risk type (along the zero-profit pooling line) plus a supplemental (undisclosed and nonexclusive) contract that brings the high-risk type to full insurance (at his own odds). We show that this outcome is extremely robust and constrained Pareto efficient. Consumer disclosure and asymmetric equilibrium information flows are critical in supporting the equilibrium.

Genetic variability in the E6 and E7 oncogenes of HPV52 and its prevalence in the Taizhou area, China

BackgroundHuman papillomavirus (HPV) 52 is one of the prevalent oncogenic HPV genotypes in East Asia. Chinese women have the highest susceptibility to the HPV52 type, but research data on HPV52 genetic variability and its carcinogenicity in China is lacking.MethodsThe present study aimed to investigate the genetic variability of HPV52 currently circulating among Chinese women by PCR sequencing the entire E6 and E7 oncogenes. HPV52 sequence alignment, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed by BioEdit software and MEGA X software.ResultsBetween 2016 and 2018, the overall HPV infection rate was 21.3%, of which HPV52 was the most prevalent high-risk type (17.2%) in the Taizhou area, China. A total of 339 single HPV52-positive samples were included in this study. We obtained 27 distinct variation patterns of HPV52 with the accession GenBank numbers ON529577-ON529603. Phylogenetic analysis showed that 96.6% of HPV52 variants belonged to lineage B, which seemed to be uniquely defined by G350T, A379G (K93R) in the E6 gene and C751T, A801G in the E7 gene. Due to the dominance of lineage B in our study population, the results could not be used to assess the association of the HPV52 (sub)lineage with the risk of cervical lesions. In addition, no significant trends were observed between the nucleotide substitutions of HPV52 variants and the risk of cervical carcinogenesis.ConclusionOur data showed that HPV52 variants were strongly biased towards lineage B. These results confirmed that cervical lesions in the Taizhou area are highly attributable to HPV52, which may be due to the high infection rate of lineage B in the population.

Epidemiological characteristics and molecular features of carbapenem-resistant Enterobacter strains in China: a multicenter genomic study

ABSTRACT Epidemiological characteristics and molecular features of carbapenem-resistant Enterobacter (CR-Ent) species remain unclear in China. In this study, we performed a genomic study on 92 isolates from Enterobacter-caused infections from a multicenter study in China. Whole genome sequencing (WGS) was used to determine the genome sequence of 92 non-duplicated CR-Ent strains collected from multiple tertiary health centres. The precise species of Enterobacter strains were identified by average nucleotide identity (ANI) and in silico DNA–DNA hybridization (isDDH). Molecular features of high-risk CR-Ent sequence type (ST) lineages and carbapenemase-encoding plasmids were determined. The result revealed that the most common human-source CR-Ent species in China was E. xiangfangensis (66/92, 71.93%), and the proportion of carbapenemase-producing Enterobacter (CP-Ent) in CR-Ent was high (72/92, 78.26%) in comparison to other global regions. Furthermore, ST171 and ST116 E. xiangfangensis were the major lineages of CP-Ent strains, and ST171 E. xiangfangensis was more likely to cause infections in older patients. Genomic analysis also highlighted the likelihood of intra-hospital/inter-hospital clonal transmission of ST171 and ST116 E. xiangfangensis. In addition, the bla NDM-harbouring IncX3-type plasmid was identified as the prevalent carbapenemase-encoding plasmid carried by CR-Ent strains, and was experimentally confirmed to be able to self-transfer with high frequency. This study detailed the genomic and clinical characteristics of CR-Ent in China in the form of multicenter for the first time. The high risk of carbapenemase-producing ST171 and ST116 E. xiangfangensis, and the bla NDM-harbouring IncX3-type plasmid were detected and emphasized.

Therapeutic Effect of Bortezomib Combined with Dag Regimen in Hyperleukocytic Acute Myeloid Leukemia

AbstractIntroduction: Hyperleukocytic acute myeloid leukemia(HAML) is a high-risk type of acute myeloid leukemia (AML), with white blood cell counts exceeding 100 x 10 ^ 9/L in peripheral blood, accounting for approximately 5%-20% of AML.Bortezomib is the first proteasome inhibitor approved by the US FDA for clinical use.The efficacy of either single agent or in combination with other agents for acute myeloid leukemia is inconclusive. DAG is commonly used as a classical chemotherapy regimen for acute myeloid leukemia.We have found that bortezomib has a therapeutic effect on acute myeloid leukemia in clinical empirical medication, so we investigated the therapeutic effect of bortezomib combined with DAG regimen on HAML. Methods:Primary hyperleukocytic leukemia cells were isolated from bone marrow of hyperleukocytic acute myeloid leukemia patients using ficoll liquid, then the primary hyperleukocytic leukemia cells were treated with bortezomib (0 nm, 5 nm, 10 nm, 20 nm, 50 nm), DAG, and bortezomib combined with DAG regimens at different concentration gradients.Cell viability was detected by flow cytometry. The HAML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of bortezomib combined with DAG regimen using the same dosing regimen as the clinical medication regimen: bortezomib 1.3 mg/m2, subcutaneous injection, 4 times a course, d1, 4, 8, and 11; doxorubicin liposome injection 5 mg/m2, intravenous drip, every other day, 5 times in total; cytarabine 10 mg/m2, subcutaneous injection, d1-14 every 12 h; and G-CSF 200 μg/m2 per day, subcutaneous injection, d1-14 days. Results: With the increase of concentration gradient, the apoptosis of HAML leukemia cells induced by bortezomib alone and DAG alone was gradually enhanced, while the viable cell count of bortezomib combined with DAG was much lower than that of bortezomib alone or DAG alone. In animal experiments, flow cytometry showed that the ratio of human leukaemia cells in bone marrow blood decreased revealed the most significant decrease in the bortezomib combined with DAG group, absolute counts of CD45 cells in the bone marrow cells of mice in each group also revealed the most significant decrease in the bortezomib combined with DAG group. Morphological examination of myelocyte smears revealed significantly fewer myeloblasts in the bortezomib combined with DAG group than in the other groups. The survival rate in the bortezomib combined with DAG group was better than in the bortezomib alone or DAG alonefor the HAML PDX model. Conclusion:Bortezomib combined with DAG regimen has synergistic killing effect on HAML and may serve as a certain clinical prospect in the treatment of hyperleukocytic acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

The Genetic Characteristics and Carbapenem Resistance Mechanism of ST307 Klebsiella pneumoniae Coharbouring blaCMY-6, blaOXA-48, and a Truncated blaNDM-1.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a common nosocomial pathogen causing severe infectious diseases, and ST307 CRKP is an emerging clone. In this study, we collected five ST307 CRKP isolates, evaluated their antimicrobial susceptibility using microbroth dilution, and their clonality and population structure by PFGE, cgMLST, and SNP-based phylogenetic analysis. Then, the genome characteristics, such as antimicrobial resistance genes and plasmid profiles, were studied by subsequent genomic analysis. The plasmid transfer ability was evaluated by conjugation, and the carbapenem resistance mechanism was elucidated by gene cloning. The results showed that all five ST307 CRKP isolates harboured blaCMY-6, blaOXA-48, and blaNDM-1; however, the end of the blaNDM-1 signal peptide was interrupted and truncated by an IS10 element, resulting in the deactivation of carbapenemase. The ST307 isolates were closely related, and belonged to the globally disseminated clade. blaOXA-48 and blaNDM-1 were located on the different mobilisable IncL/M- and IncA/C2-type plasmids, respectively, and either the pOXA-48 or pNDM-1 transconjugants were ertapenem resistant. Gene cloning showed that blaCMY-6 could elevate the MICs of carbapenems up to 64-fold and was located on the same plasmid as blaNDM-1. In summary, ST307 is a high-risk clone type, and its prevalence should be given additional attention.

Immunohistochemical Evaluation of S100, Alpha-Smooth Muscle Actin, Podoplanin, Matrix Metalloproteinase 13, and Human Epidermal Growth Factor Receptor 2neu Markers in Basal Cell Carcinoma Variants.

Background Variants of basal cell carcinoma (BCC) appear to behave biologically differently. Several histological patterns impact the concept of low-risk (indolent) and high-risk (aggressive) types in the head and neck. This study aims to assess the biological behavior of BCC variants by immunohistochemical expression of S100, alpha-smooth muscle actin (α-SMA), podoplanin, matrix metalloproteinase 13 (MMP-13), andhuman epidermal growth factor receptor 2 (HER2)neu biomarkers. Methodology A total of 65 paraffin-embedded tissue blocks of BCC of the head and neck were retrieved from the collections of the Histopathology Department of the Medical City Teaching Complex and the Ghazi Al-Harerri Hospital at the University of Baghdad's College of Dentistry, spanning the years 2015 through 2021. S100, α-SMA, podoplanin, MMP-13, and HER2neu biomarkers were used to perform immunohistochemical analysis (Abcam). Results This study noticed different expressions of S100, α-SMA, podoplanin, MMP-13, and HER2neu between different variants. There was no immunohistochemical expression in perineural invasion with all cases of BCC variants. The highest expression was seen in HER2neu, MMP-13, and α-SMA with aggressive histological patterns. There was no podoplanin lymphatic vessel density immunoexpressing in all variants, while tumoral podoplanin showed a significant difference in all variants. HER2neu was correlated with all other biomarkers. Conclusions HER2neu, MMP-13, and α-SMA biomarkers can be used as diagnostic markers to predict the aggressive biological behavior of BCC tumors.

Immunogenicity and safety of two novel human papillomavirus 4- and 9-valent vaccines in Chinese women aged 20–45 years: A randomized, blinded, controlled with Gardasil (type 6/11/16/18), phase III non-inferiority clinical trial

BackgroundHuman papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent). Methods1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20–26, 27–35, or 36–45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference > −10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio > 0.5. ResultsAmong the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded −10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios > 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths. ConclusionsThis study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.