Medial sural artery perforator free flap versus radial forearm free flap in oral cavity reconstruction and donor site morbidity.

OBJECTIVE: Radial Forearm Free flap (RFFF) is widely used in head and neck reconstruction, yet its donor site defect remains a significant drawback. The Medial Sural Artery Perforator Free Flap (MSAPFF) is considered an alternative flap to RFFF. This study aims to comprehensively analyze their characteristics, outcomes, and their impact on patient quality of life. METHODS: All patients who underwent oral cavity reconstruction using RFFF and MSAPFF between February 2017 and April 2023 were included in this study. Flap characteristics, outcomes and post-operative complications were recorded and compared. Subjective donor site morbidity, aesthetic and functional results, and quality of life were also analyzed. RESULTS: The study included 76 patients: 37 underwent reconstruction with RFFF, and 39 with MSAPFF. There was no significance difference between the RFFF and MSAPFF regarding the success rate (97.2% vs 97.4%), flap size (4.8 × 8.8 cm2 vs 5 × 9.8 cm2), hospital of stay (15.5 days vs 13.5 days) and recipient site complications (P > 0.05). However, MSAPFF showed larger flap thickness (P = 0.001), smaller arterial caliber (P = 0.008), shorter pedicle length (P = 0.001), and longer harvesting time (P < 0.001). No significant difference was observed between the pre-and postoperative ranges of wrist and ankle movements or in recipient site complications. MSAPFF showed a significant difference in donor site morbidity (P < 0.05). CONCLUSION: The MSAPFF is an excellent alternative to the RFFF for repairing oral cavity defects, with additional advantage of a well-hidden scar on the posterior calf, a larger flap thickness, accepted pedicle length and arterial caliber. However, one should consider the harvesting time and surgical skills required in comparison to the RFFF. CLINICAL RELEVANCE: The study highlights the importance of the MSAPFF as an alternative option for RFFF with less donor site morbidity and high success rate in oral cavity reconstruction and improved patient Quality of life after ablative surgery.

Response surface methodology optimization of extraction and enrichment conditions of total triterpenoid saponins from Celosiae Semen and evaluation of its lipid-lowering activity.

The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug.

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer.

Radical prostatectomy is a primary treatment option for localized prostate cancer (PCa), although high rates of recurrence are commonly observed postsurgery. Photodynamic therapy (PDT) has demonstrated efficacy in treating nonmetastatic localized PCa with a low incidence of adverse events. However, its limited efficacy remains a concern. To address these issues, various organic polymeric nanoparticles (OPNPs) loaded with photosensitizers (PSs) that target prostate cancer have been developed. However, further optimization of the OPNP design is necessary to maximize the effectiveness of PDT and improve its clinical applicability. This Review provides an overview of the design, preparation, methodology, and oncological aspects of OPNP-based PDT for the treatment of PCa.

Suppression of the SLC7A11/glutathione axis causes ferroptosis and apoptosis and alters the mitogen-activated protein kinase pathway in nasopharyngeal carcinoma.

SLC7A11 is a unit of the glutamate cystine antiporter Xc- system. It functions to import cystine for glutathione biosynthesis and maintains the redox balance in cells. Sorafenib inhibits the transporter activity of SLC7A11. The use of sorafenib has been approved in the treatment of multiple cancers. However, at present, our understanding of the mechanism of SLC7A11 and sorafenib in nasopharyngeal carcinoma (NPC) remains limited. We found that the expression of SLC7A11 was upregulated in NPC. A high SLC7A11 expression was associated with poor prognosis, metastasis, and an advanced T stage, which can be used as an independent prognostic indicator of NPC. In vitro, we observed that NPC cells relied on cystine for survival. Targeting SLC7A11 resulted in glutathione biosynthesis limitation, intracellular reactive oxygen species accumulation, lipid peroxides, ferroptosis, and apoptosis. Meanwhile, it altered mitogen activated protein kinase pathway, including p38 activation but ERK inhibition in NPC. This limited the proliferation of NPC cells. Sorafenib inhibited the proliferation and induced the death of NPC cells in vivo. In conclusion, SLC7A11 plays an important role in the occurrence and progression of NPC and may be a novel target for NPC treatment.

Mutational landscape of head and neck cancer and cervical cancer in Chinese and Western population.

BACKGROUND: We aimed to unbiasedly map the genetic mutation profile of HNSC and CESC associated with HPV status in the Chinese population (SYSU-cohort) and compare them with Western population (TCGA-cohort). METHODS: Fifty-one HNSC patients (SYSU-HNSC) and 38 CESC patients (SYSU-CESC) were enrolled in this study. Genomic alterations were examined, and the profile was produced using the YuanSuTM450 gene panel (OrigiMed, Shanghai, China). The altered genes were inferred and compared to Western patients from TCGA cohorts. RESULTS: Compared to the TCGA-HNSC cohort, FGFR3 mutation was identified as a novel target in SYSU-HNSC with therapeutic potential. Compared to the TCGA-CESC cohort, some epigenetic regulation-associated genes were frequently mutated in SYSU-CESC cohort (KMT2C, KMT2D, KDM5C, KMT2A). CONCLUSION: In summary, our study provides unbiased insights into the genetic landscape of HNSC and CESC in the Chinese population and highlights potential novel therapeutic targets that may benefit Chinese patients.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Perioperative risk factors impact on intensive care unit length of stay (ICU length of stay) in oral squamous cell carcinoma.

BACKGROUND: The trend in postoperative care for free flap patients is to deescalate from routine ICU admission into a specialty recovery unit. This study aims to investigate the predictive parameters in a routine perioperative clinical assessment that are expected to be directly correlated with prolonged ICU length of stay in at-risk patients who received oral reconstructive surgery for squamous cell carcinoma (OSCC). METHODS: All patients who underwent ablative surgery for OSCC with free flap reconstruction and were managed in the ICU were included in this study. The primary outcome was ICU-length of stay. Perioperative, operative and postoperative parameters were analyzed using single test ( t-test, ANOVA analysis, correlation coefficients, effect size) and multivariate regression test. The P-value was set as < 0.005 to be considered statically significant. RESULTS: The study included 136 homogeneous patients, with a mean ICU length of stay of 4.5 (± 4.43 day). Patients with pre-operative positive renal dysfunction (P = 0.004), peripheral vascular disease (P < 0.001), postoperative complications (P = 0.028) or positive heart failure class III (P < 0.001 ) were recognized as at-risk patients for a significantly longer ICU length of stay. CONCLUSION: Patients with perioperative severe renal dysfunction, peripheral vascular disease, postoperative complication or high NYHA class are prone to have a significantly longer ICU length of stay. Several factors were considered as confounders contributing to increased ICU management time in combination with other variables. Additionally, in highly risk patient, the presence of the highly trained medical support, including the appropriate nursing care, is more critical than those patients without these risk factors.

Effectiveness and cost-effectiveness of human papillomavirus vaccination strategies among men who have sex with men in China: a modeling study.

Introduction: The health and economic benefits of human papillomavirus (HPV) vaccination targeted at men who have sex with men (MSM) in developing settings have been rarely assessed. This study aimed to evaluate the effectiveness and cost-effectiveness of different HPV vaccination strategies among MSM in China. Methods: A Markov model was developed to simulate HPV transmission dynamics among a total of 30.73 million MSM in China. The corresponding natural history included 6 states: susceptible, infected with low-risk subtypes, high-risk subtypes, anogenital warts and anal cancer, and deaths from anal cancer. MSM were divided into three age groups with cut-off points of 27 and 45 years. Alternative vaccination strategies were built by allocating bivalent, quadrivalent, nine-valent, or no vaccine to each of the groups. We generated the prevented infections and deaths by vaccination compared with baseline (no vaccination) and calculated incremental cost-effectiveness ratios (ICERs) to determine the optimal strategy. Results: The model showed that in 10 years, at baseline, the existing cases of anogenital warts would reach 5,464,225 (IQR, 4,685,708-6,174,175); that of anal cancer would reach 1,922.95 (1,716.56-2,119.93), resulting in 940.55 (732.27-1,141.87) deaths. Under 50% vaccination coverage among one age group, the prevented cases of anogenital warts were maximized with quadrivalent vaccines allocated to MSM aged 27-45 years; that of anal cancer were maximized when offering nine-valent vaccines to the same group. Under 50% vaccination coverage among all groups, the lowest ICER (34,098.09 USD/QALY, 31,146.54-37,062.88) was reached when only quadrivalent vaccines were provided. Based on this strategy, when the annual vaccination rate increased by 30%, the ICER (33,521.75 USD/QALY, 31,040.73-36,013.92) would fall below three times China's per capita GDP. When the vaccine price decreased by 60%, the ICER was reduced to 7,344.44 USD/QALY (4,392.89-10,309.23), indicating good cost-effectiveness taking China's per capita GDP as a threshold. Conclusions: HPV vaccination can effectively reduce the prevalence and mortality of related diseases among MSM in China, especially quadrivalent vaccines for anogenital warts and nine-valent vaccines for anal cancer. MSM aged 27-45 years were the optimal group for vaccination. Annual vaccination and appropriate adjustment of vaccine price are necessary to further improve the cost-effectiveness.

Global and Regional Estimate of HIV-Associated Stroke Burden: A Meta-Analysis and Population Attributable Modeling Study.

BACKGROUND: This study aimed to determine the correlation between human-immunodeficiency-virus (HIV) infection and stroke, as well as to estimate the global, regional, and national burden of HIV-associated stroke. METHODS: A registered meta-analysis was performed by searching PubMed, Embase, and Web of Science for relevant literature up to October 31, 2022. The pooled relative risk of stroke in HIV-infected people was calculated using a random-effects model. HIV prevalence and disability-adjusted life years (DALYs) datasets were obtained from the Joint United Nations Program on HIV and AIDS, and the Global Health Data Exchange, respectively. The population attributable fraction was estimated and delivered to calculate the HIV-associated DALYs of stroke from 1990 to 2019, at the global, regional, and national levels. Pearson correlation analysis were conducted to assess the correlation between the age-standardized rate or estimated annual percentage changes and the sociodemographic index. RESULTS: Out of 10 080 identified studies, 11 were included in this meta-analysis. Compared with individuals without HIV-infection, the pooled relative risk of stroke in HIV-infected individuals was 1.40 (95% CI, 1.18-1.65). From 1990 to 2019, the global population attributable fraction of HIV-associated stroke increased almost 3-fold, while the HIV-associated DALYs increased from 18 595 (95% CI, 7485-31 196) in 1990 to 60 684 (95% CI, 24 281-101 894) in 2019. Meanwhile, HIV-associated DALYs varied by region, with Eastern and Southern Africa having the highest value of 126 160 in 2019. Moreover, countries with middle social development index were shouldering the highest increase trend of the HIV-associated DALYs age-standardized rates. CONCLUSIONS: HIV-infected individuals face a significantly higher risk of stroke, and the global burden of HIV-associated stroke has increased over the past 3 decades, showing regional variations. Eastern and Southern Africa bear the highest burden, while Eastern Europe and Central Asia have seen significant growth. Health care providers, researchers, and decision-makers should give increased attention to stroke prevention and management in HIV-endemic areas. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42022367450.

Stone attenuation on computer tomography helps surgeons make decisions between miniaturized percutaneous nephrolithotomy or retrograde intrarenal surgery for lower pole stones: a retrospective study.

A retrospective study was performed on 200 patients who underwent miniaturized percutaneous nephrolithotomy (mini-PCNL) or retrograde intrarenal surgery (RIRS) for 10-20 mm sized lower pole renal calculi to investigate the relationship between computed tomography (CT) attenuation of calculi and surgical outcomes. CT was used to examine the location, size, and CT attenuation values of the calculi. Additionally, the operation time, hospital stay, hemoglobin (Hb) reduction, stone-free rate (SFR), and complication rate were also meticulously documented and subjected to comparative analysis. Complications were assessed using the Clavien-Dindo grading system. We observed no significant differences in hospitalization data and follow-up outcomes, except for a longer hospital stay and higher Hb drops in patients receiving mini-PCNL. Statistical analysis revealed an association between CT attenuation and operation time. Compared with mini-PCNL, RIRS could reduce bleeding, hospital stay, surgery time, and complications for 10-20 mm sized lower pole kidney stones with CT values < 1000 HU. RIRS resulted in longer operation time and lower stone-free rates despite shorter hospital stays and less bleeding than mini-PCNL for stones with CT values > 1000 HU. Therefore, selecting an appropriate surgical method based on CT attenuation might improve outcomes. For patients with stone attenuation values < 1000 HU, RIRS is the recommended option. When stone attenuation values > 1000 HU, the surgical method should be chosen based on the patient's individual situation.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and tumor microenvironment, overcoming multiple obstacles of CAR T therapy for solid tumors.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.

Metabolomics Reveal the Regulatory Effect of Polysaccharides from Fermented Barley Bran Extract on Lipid Accumulation in HepG2 Cells.

Barley bran has potential bioactivities due to its high content of polyphenols and dietary fiber, etc. Fermentation has been considered as an effective way to promote the functional activity of food raw materials. In this study, polysaccharides from barley bran extract fermented by Lactiplantibacillus plantarum dy-1 (FBBE-PS) were analyzed, and its effects on lipid accumulation and oxidative stress in high-fat HepG2 cells induced by sodium oleate were evaluated. The results showed that the molecular weight decreased and monosaccharide composition of polysaccharides changed significantly after fermentation. In addition, 50 µg/mL FBBE-PS could reduce the triglyceride (TG) content and reaction oxygen species (ROS) level in high-fat HepG2 cells by 21.62% and 30.01%, respectively, while increasing the activities of superoxide dismutase (SOD) and catalase (CAT) represented by 64.87% and 22.93%, respectively. RT-qPCR analysis revealed that FBBE-PS could up-regulate the lipid metabolism-related genes such as ppar-α, acox-1 and cpt-1α, and oxidation-related genes such as nrf2, ho-1, nqo-1, sod1, cat, etc. The metabolomics analysis indicated that FBBE-PS could alleviate lipid deposition by inhibiting the biosynthesis of unsaturated fatty acids, which is consistent with the downregulation of scd-1 expression. It is demonstrated that fermentation can alter the properties and physiological activities of polysaccharides in barley bran, and FBBE-PS exhibited an alleviating effect on lipid deposition and oxidative stress in high-fat cells.

Comparative transcriptomics and co-expression networks reveal cultivar-specific molecular signatures associated with reproductive-stage cold stress in rice.

KEY MESSAGE: The resistance of Huaidao5 results from the high constitutive expression of tolerance genes, while that of Huaidao9 is due to the cold-induced resistance in flag leaves and panicles. The regulation mechanism of rice seedlings' cold tolerance is relatively clear, and knowledge of its underlying mechanisms at the reproductive stage is limited. We performed differential expression and co-expression network analyses to transcriptomes from panicle and flag leaf tissues of a cold-tolerant cultivar (Huaidao5), and a sensitive cultivar (Huaidao9), under reproductive-stage cold stress. The results revealed that the expression levels of genes in stress-related pathways such as MAPK signaling pathway, diterpenoid biosynthesis, glutathione metabolism, plant-pathogen interaction and plant hormone signal transduction were constitutively highly expressed in Huaidao5, especially in panicles. Moreover, the Hudaidao5's panicle sample-specific (under cold) module contained some genes related to rice yield, such as GW5L, GGC2, SG1 and CTPS1. However, the resistance of Huaidao9 was derived from the induced resistance to cold in flag leaves and panicles. In the flag leaves, the responses included a series of stress response and signal transduction, while in the panicles nitrogen metabolism was severely affected, especially 66 endosperm-specific genes. Through integrating differential expression with co-expression networks, we predicted 161 candidate genes (79 cold-responsive genes common to both cultivars and 82 cold-tolerance genes associated with differences in cold tolerance between cultivars) potentially affecting cold response/tolerance, among which 85 (52.80%) were known to be cold-related genes. Moreover, 52 (65.82%) cold-responsive genes (e.g., TIFY11C, LSK1 and LPA) could be confirmed by previous transcriptome studies and 72 (87.80%) cold-tolerance genes (e.g., APX5, OsFbox17 and OsSTA109) were located within QTLs associated with cold tolerance. This study provides an efficient strategy for further discovery of mechanisms of cold tolerance in rice.

Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response.

Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC.

Evidence for exposure biomarkers in dictamnine-induced liver injury resulting from metabolic activation in vitro and in mice.

Dictamnine (DTN), a furoquinoline alkaloid isolated from Dictamni Cortex, is responsible for the liver injury caused by Dictamni Cortex and the preparations. Discovering new biomarkers with high specificity and sensitivity for diagnosis and tracing the source of DTN-induced liver injury is urgently needed. Considering that metabolic activation of DTN has been suggested as a primary trigger initiating hepatotoxicity, the present study aimed to investigate the bio-activation process of DTN in vitro and in mice and to explore whether the adducts could be developed as exposure biomarkers. When trapping with N-acetyl-cysteine (NAC) and glutathione (GSH) in mouse liver microsomes and CYP3A4 overexpressed L02 cells, two isomers of DTN-NAC adducts were detected in both systems and one DTN-GSH adduct was found in mouse liver microsomes. As expected, one DTN-NAC adduct was also found in plasma and bile of mice with liver injury after DTN exposure. Moreover, mouse liver microsomes were used to simulate the conjugation of serum albumin with metabolically activated DTN. The sole modified peptide 25 DAHKSEVAHR34 was found, and the oxidative metabolites of DTN might bind to the side chain amino of albumin at Arg34. The above findings not only provided confirmative evidence that DTN was metabolically activated to induce liver injury but also suggested that the adducts had the potential to be developed as exposure biomarkers of DTN-induced liver injury.

Gastric cancer incidence trends in China and Japan from 1990 to 2019: Disentangling age-period-cohort patterns.

BACKGROUND: Recent data have shown divergent trends in gastric cancer (GC) incidence between China and Japan; however, the cause for has not been explored. METHODS: We retrieved GC incidence data from 1990 to 2019 from the Global Burden of Disease study, stratified by sex for both countries. We analyzed annual average percentage change (AAPC) via a joinpoint regression model and estimated the effects of age, period, and cohort via the age-period-cohort model. RESULTS: The age-standardized incidence rate trends for GC decreased in both countries and both sexes, but the reduction was more pronounced in Japan because the AAPC for Japanese males (AAPC = -2.65%; 95% CI, -2.98 to -2.32) was eight times greater than that of Chinese males (AAPC = -0.30%; 95% CI, -0.5 to -0.09). The age and cohort effects on the trend are similar in both countries: the risk of GC incidence increased with age among the Chinese and the Japanese but was lower among younger birth cohorts. The two countries showed contrasting trends over the study period; although the risk of GC rapidly decreased for Japanese males and females, it increased by twofold among Chinese males. CONCLUSIONS: The period effect is the main reason for the divergent trends in age-standardized incidence rate for GC in China and Japan. By comparing national cancer control programs in both countries, we concluded that countries with a high prevalence of GC, such as China, can learn from Japan's experience in controlling GC by actively conducting national population screening, which is expected to facilitate both prevention and treatment of GC. LAY SUMMARY: More than one-half of all new gastric cancer (GC) worldwide occur in China and Japan, but the reasons for the different incidence trends have not been thoroughly analyzed. Analysis using the age-period-cohort model confirmed that the cohort effect was the main reason for the decline in age-standardized incidence rate (ASIR) for GC and that the period effect may be the main reason for the divergent trends in gastric cancer ASIR in China and Japan.

Incidence and Clearance of Anal Human Papillomavirus Infection in 16 164 Individuals, According to Human Immunodeficiency Virus Status, Sex, and Male Sexuality: An International Pooled Analysis of 34 Longitudinal Studies.

BACKGROUND: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized. METHODS: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants. RESULTS: Human papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection. CONCLUSIONS: This robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

Effect of thread depth and thread pitch on the primary stability of miniscrews receiving a torque load : A finite element analysis.

PURPOSE: We have been developing a new type of miniscrew to specifically withstand orthodontic torque load. This study aimed to investigate the effect of thread depth and thread pitch on the primary stability of these miniscrews if stressed with torque load. METHODS: Finite element analysis (FEA) was used to evaluate the primary stability of the miniscrews. For thread depth analysis, the thread depth was set to 0.1-0.4 mm to construct 7 models. For thread pitch analysis, the thread pitch was set to 0.4-1.0 mm to construct another 7 models. A torque load of 6 Nmm was applied to the miniscrew, and the other parameters were kept constant for the analyses. Maximum equivalent stress (Max EQV) of cortical bone and maximum displacement of the miniscrews (Max DM) were the indicators for primary stability of the miniscrew in the 14 models. RESULTS: In the thread depth analysis, Max DM increased as the miniscrew thread depth increased, while Max EQV was smallest in model 3 (thread depth = 0.2, Max EQV = 8.91 MPa). In the pitch analysis, with an increase of the thread pitch, Max DM generally exhibited a trend to increase, while Max EQV of cortical bone showed a general trend to decrease. CONCLUSION: Considering the data of Max DM and Max EQV, the most appropriate thread depth and thread pitch of the miniscrews in our model was 0.2 and 0.7 mm, respectively. This knowledge may effectively improve the primary stability of newly developed miniscrews.

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen-induced metabolic activation and hepatotoxicity.

Psoralen and isopsoralen are the pharmacologically important but hepatotoxic components in Psoraleae Fructus. The purpose of this study was to reveal the underlying mechanism of psoralen/isopsoralen-induced hepatotoxicity. Initially, we applied integrated analyses of transcriptomic and metabolomic profiles in mice treated with psoralen and isopsoralen, highlighting the xenobiotic metabolism by cytochromes P450 as a potential pathway. Then, with verifications of expression levels by qRT-PCR and western blot, affinities by molecular docking, and metabolic contributions by recombinant human CYP450 and mouse liver microsomes, CYP1A2 was screened out as the key metabolic enzyme. Afterwards, CYP1A2 induction and inhibition models in HepG2 cells and mice were established to verify the role of CYP1A2, demonstrating that induction of CYP1A2 aggravated the hepatotoxicity, and conversely inhibition alleviated the hepatotoxic effects. Additionally, we detected glutathione adducts with reactive intermediates of psoralen and isopsoralen generated by CYP1A2 metabolism in biosystems of recombinant human CYP1A2 and mouse liver microsomes, CYP1A2-overexpressed HepG2 cells, mice livers and the chemical reaction system using UPLC-Q-TOF-MS/MS. Ultimately, the high-content screening presented the cellular oxidative stress and relevant hepatotoxicity due to glutathione depletion by reactive intermediates. In brief, our findings illustrated that CYP1A2-mediated metabolic activation is responsible for the psoralen/isopsoralen-induced hepatotoxicity.