A Genomics-Driven Artificial Intelligence-Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating Mechanisms.

Artificial intelligence (AI)-systems can improve cancer diagnosis, yet their development often relies on subjective histological features as ground truth for training. Here, we developed an AI-model applied to histological whole-slide images (WSIs) using CDH1 bi-allelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted CDH1 bi-allelic mutations (accuracy=0.95) and diagnosed ILC (accuracy=0.96). A total of 74% of samples classified by the AI-model as having CDH1 bi-allelic mutations but lacking these alterations displayed alternative CDH1 inactivating mechanisms, including a deleterious CDH1 fusion gene and non-coding CDH1 genetic alterations. Analysis of internal and external validation cohorts demonstrated 0.95 and 0.89 accuracy for ILC diagnosis, respectively. The latent features of the AI-model correlated with human-explainable histopathologic features. Taken together, this study reports the construction of an AI-algorithm trained using a genetic rather than histologic ground truth that can robustly classify ILCs and uncover CDH1 inactivating mechanisms, providing the basis for orthogonal ground truth utilization for development of diagnostic AI-models applied to WSI.

Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.

PURPOSE: The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase. EXPERIMENTAL DESIGN: We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings. RESULTS: Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients. CONCLUSIONS: Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments.

Development and validation of the Social Touch Experiences and Attitudes Questionnaire-Chinese version (STEAQ-C): How interpersonal touch relates to subclinical traits and symptoms.

Social touch has a vital role in human development and psychological well-being. However, there is a lack of measures assessing individual differences in social touch experiences and attitudes, especially under Eastern cultures. This study developed the Social Touch Experiences and Attitudes Questionnaire - Chinese version (STEAQ-C) and examined its psychometric properties with healthy young Chinese adults. In Study 1, an item pool was generated and principal component analysis (PCA) was used to identify the factor structure of the STEAQ. Study 2 recruited an independent sample and examined its reliability and validity. Network analysis further explored the interrelations between social touch and a variety of subclinical traits and symptoms. PCA identified four factors of the STEAQ-C, relating to childhood touch experiences, current touch with intimate partners, with family and friends, and with unfamiliar people. Study 2 confirmed the four-factor structure and upheld its internal consistency and stability. Positive attitudes towards and greater experiences of social touch were negatively correlated with sensory over-responsiveness and sensory hyposensitivity, as well as childhood trauma particularly emotional neglect, supporting the convergent validity. Evidence of criterion-related validity was accrued via its concurrent and predictive associations with secure attachment style, higher levels of social competence, and lower levels of social anxiety. Network analysis highlighted altered perception of social touch may be a shared feature for psychiatric conditions with social dysfunctions (e.g., autism, social anxiety and negative schizotypy). The newly-developed STEAQ-C may be a timely tool in assessing social touch experiences and attitudes under Eastern cultures.

DOT1L-mediated RAP80 methylation promotes BRCA1 recruitment to elicit DNA repair.

Breast Cancer Type 1 Susceptibility Protein (BRCA1) is a tumor-suppressor protein that regulates various cellular pathways, including those that are essential for preserving genome stability. One essential mechanism involves a BRCA1-A complex that is recruited to double-strand breaks (DSBs) by RAP80 before initiating DNA damage repair (DDR). How RAP80 itself is recruited to DNA damage sites, however, is unclear. Here, we demonstrate an intrinsic correlation between a methyltransferase DOT1L-mediated RAP80 methylation and BRCA1-A complex chromatin recruitment that occurs during cancer cell radiotherapy resistance. Mechanistically, DOT1L is quickly recruited onto chromatin and methylates RAP80 at multiple lysines in response to DNA damage. Methylated RAP80 is then indispensable for binding to ubiquitinated H2A and subsequently triggering BRCA1-A complex recruitment onto DSBs. Importantly, DOT1L-catalyzed RAP80 methylation and recruitment of BRCA1 have clinical relevance, as inhibition of DOT1L or RAP80 methylation seems to enhance the radiosensitivity of cancer cells both in vivo and in vitro. These data reveal a crucial role for DOT1L in DDR through initiating recruitment of RAP80 and BRCA1 onto chromatin and underscore a therapeutic strategy based on targeting DOT1L to overcome tumor radiotherapy resistance.

Tomato bacterial wilt disease outbreaks are accompanied by an increase in soil antibiotic resistance.

The presence of soil-borne disease obstacles and antibiotic resistance genes (ARGs) in soil leads to serious economic losses and health risks to humans. One area in need of attention is the evolution of ARGs as pathogenic soil gradually develops, which introduces uncertainty to the dynamic ability of conventional farming models to predict ARGs. Here, we investigated variations in tomato bacterial wilt disease accompanied by the resistome by metagenomic analysis in soils over 13 seasons of monoculture. The results showed that the abundance and diversity of ARGs and mobile genetic elements (MGEs) exhibited a significant and positive correlation with R. solanacearum. Furthermore, the binning approach indicated that fluoroquinolone (qepA), tetracycline (tetA), multidrug resistance genes (MDR, mdtA, acrB, mexB, mexE), and ß-lactamases (ampC, blaGOB) carried by the pathogen itself were responsible for the increase in overall soil ARGs. The relationships between pathogens and related ARGs that might underlie the breakdown of soil ARGs were further studied in R. solanacearum invasion pot experiments. This study revealed the dynamics of soil ARGs as soil-borne diseases develop, indicating that these ecological trends can be anticipated. Overall, this study enhances our understanding of the factors driving ARGs in disease-causing soils.

Radical Deoxygenative Three-Component Reaction of Alcohols, Aryl Alkenes, and Cyanopyridines.

We report herein a deoxygenative radical multicomponent reaction involving alcohols, aryl alkenes, and cyanopyridine under photoredox conditions. This method is photoredox-neutral, suitable for late-stage modification, and compatible with a wide array of alcohols as alkyl radical sources, including primary, secondary, and tertiary alcohols. This reaction comprises a radical relay mechanism encompassing the Giese addition of aryl alkenes by alkyl radicals, followed by the decyanative pyridination of benzyl radicals.

The Contact Properties of Monolayer and Multilayer MoS2-Metal van der Waals Interfaces.

The contact resistance formed between MoS2 and metal electrodes plays a key role in MoS2-based electronic devices. The Schottky barrier height (SBH) is a crucial parameter for determining the contact resistance. However, the SBH is difficult to modulate because of the strong Fermi-level pinning (FLP) at MoS2-metal interfaces. Here, we investigate the FLP effect and the contact types of monolayer and multilayer MoS2-metal van der Waals (vdW) interfaces using density functional theory (DFT) calculations based on Perdew-Burke-Ernzerhof (PBE) level. It has been demonstrated that, compared with monolayer MoS2-metal close interfaces, the FLP effect can be significantly reduced in monolayer MoS2-metal vdW interfaces. Furthermore, as the layer number of MoS2 increases from 1L to 4L, the FLP effect is first weakened and then increased, which can be attributed to the charge redistribution at the MoS2-metal and MoS2-MoS2 interfaces. In addition, the p-type Schottky contact can be achieved in 1L-4L MoS2-Pt, 3L MoS2-Au, and 2L-3L MoS2-Pd vdW interfaces, which is useful for realizing complementary metal oxide semiconductor (CMOS) logic circuits. These findings indicated that the FLP and contact types can be effectively modulated at MoS2-metal vdW interfaces by selecting the layer number of MoS2.

Increased Synthetic Cytotoxicity of Combinatorial Chemoradiation Therapy in Homologous Recombination Deficient Tumors.

PURPOSE: Homologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with radiation therapy (RT), leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit. METHODS AND MATERIALS: Sensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using 4 assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar score (large-scale state transitions [LST]), and clonogenic survival assays. Whole-genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple-negative breast cancer was performed and HRD was defined using HRDetect. RESULTS: BRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2 µM cisplatin and 6 Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2 Gy and cisplatin 20 µM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients in the phase 2 trial, one achieved a pathologic complete response with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without a pathologic complete response. CONCLUSIONS: HRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests, or mutational signatures, appear to be significantly more sensitive to c-RT compared with isogenic controls or tumors without HRD mutational signatures. HRD tumors may be exquisitely sensitive to c-RT which warrants further clinical investigation to guide a precision oncology approach.

Predictive models for functional cure in patients with CHB receiving PEG-IFN therapy based on HBsAg quantification through meta-analysis.

BACKGROUND AND AIMS: The efficacy of achieving HBsAg clearance through pegylated interferon (PEG-IFNα) therapy in patients with chronic hepatitis B (CHB) remains uncertain, especially regarding the probability of achieving functional cure among patients with varying baseline HBsAg levels. We aimed to investigate the predictive value of HBsAg quantification for HBsAg seroclearance in CHB patients undergoing PEG-IFNα treatment. METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library up to January 11, 2022. Subgroup analyses were performed for HBeAg-positive and HBeAg-negative patients, PEG-IFNα monotherapy and PEG-IFNα combination therapy, treatment-naive and treatment-experienced patients, and patients with or without liver cirrhosis. RESULTS: This predictive model incorporated 102 studies. The overall HBsAg clearance rates at the end of treatment (EOT) and the end of follow-up (EOF) were 10.6% (95% CI 7.8-13.7%) and 11.1% (95% CI 8.4-14.1%), respectively. Baseline HBsAg quantification was the most significant factor. According to the model, it is projected that when baseline HBsAg levels are 100, 500, 1500, and 10,000 IU/ml, the HBsAg clearance rates at EOF could reach 53.9% (95% CI 40.4-66.8%), 32.1% (95% CI 24.8-38.7%), 14.2% (95% CI 9.8-18.8%), and 7.9% (95% CI 4.2-11.8%), respectively. Additionally, treatment-experienced patients with HBeAg-negative status, and without liver cirrhosis exhibited higher HBsAg clearance rates after PEG-IFNα treatment. CONCLUSION: A successful predictive model has been established to predict the achievement of functional cure in CHB patients receiving PEG-IFNα therapy.

Imaging characteristics and treatment strategies for carotid artery occlusion caused by skull base fracture: Three case reports.

BACKGROUND: Traumatic internal carotid artery (ICA) occlusion is a rare complication of skull base fractures, characterized by high mortality and disability rates, and poor prognosis. Therefore, timely discovery and correct management are crucial for saving the lives of such patients and improving their prognosis. This article retrospectively analyzed the imaging and clinical data of three patients, to explore the imaging characteristics and treatment strategies for carotid artery occlusion, combined with severe skull base fractures. CASE SUMMARY: This case included three patients, all male, aged 21, 63, and 16 years. They underwent plain film skull computed tomography (CT) examination at the onset of their illnesses, which revealed fractures at the bases of their skulls. Ultimately, these cases were definitively diagnosed through CT angiography (CTA) examinations. The first patient did not receive surgical treatment, only anticoagulation therapy, and recovered smoothly with no residual limb dysfunction (Case 1). The other two patients both developed intracranial hypertension and underwent decompressive craniectomy. One of these patients had high intracranial pressure and significant brain swelling postoperatively, leading the family to choose to take him home (Case 2). The other patient also underwent decompressive craniectomy and recovered well postoperatively with only mild limb motor dysfunction (Case 3). We retrieved literature from PubMed on skull base fractures causing ICA occlusion to determine the imaging characteristics and treatment strategies for this type of disease. CONCLUSION: For patients with cranial trauma combined with skull base fractures, it is essential to complete a CTA examination as soon as possible, to screen for blunt cerebrovascular injury.

APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer 1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

Photodynamic-Assisted Electrochemiluminescence Enhancement toward Advanced BODIPY for Precision Diagnosis of Parkinson.

Nowadays, signal enhancement is imperative to increase sensitivity of advanced ECL devices for expediting their promising applications in clinic. In this work, photodynamic-assisted electrochemiluminescence (PDECL) device was constructed for precision diagnosis of Parkinson, where an advanced emitter was prepared by electrostatically linking 2,6-dimethyl-8-(3-carboxyphenyl)4,4'-difluoroboradiazene (BET) with 1-butyl-3-methylimidazole tetrafluoroborate ([BMIm][BF4]). Specifically, protoporphyrin IX (PPIX) can trigger the photodynamic reaction under light irradiation with a wavelength of 450 nm to generate lots of singlet oxygen (1O2), showing a 2.43-fold magnification in the ECL responses. Then, the aptamer (Apt) was assembled on the functional BET-[BMIm] for constructing a "signal off" ECL biosensor. Later on, the PPIX was embedded into the G-quadruplex (G4) of the Apt to magnify the ECL signals for bioanalysis of α-synuclein (α-syn) under light excitation. In the optimized surroundings, the resulting PDECL sensor has a broad linear range of 100.0 aM ∼ 10.0 fM and a low limit of detection (LOD) of 63 aM, coupled by differentiating Parkinson patients from normal individuals according to the receiver operating characteristic (ROC) curve analysis of actual blood samples. Such research holds great promise for synthesis of other advanced luminophores, combined with achieving an early clinical diagnosis.

Bibliometric and visualized analysis of type 2 diabetic osteoporosis from 2013 to 2022.

Type 2 diabetic osteoporosis (T2DOP) has received increasing attention from researchers. In this study, a total of 453 publications related to T2DOP from 2013 to 2022 were analyzed using bibliometric and visual analysis to identify the research trends and research hotspots in the field of T2DOP. PURPOSE: The objective of this study was to conduct a comprehensive bibliometric analysis of T2DOP-related publications from 2013 to 2022 to determine global research trends in T2DOP in terms of number of publications, countries/regions, institutions, authors, journals, funding agencies, and keywords. METHODS: All data were collected from the Web of Science Core Collection (WoSCC). All original research publications regarding T2DOP from 2013 to 2022 were retrieved. VOSviewer and Microsoft Office Excel were used to conduct the bibliometric and visual analysis. RESULTS: From 2013 to 2022, 515 relevant publications were published, with a peak in 2022 in the annual number of publications. The countries leading the research were USA and China. Sugimoto was the most influential authors. Capital Medical University and Nanjing Medical University were the most prolific institutions. Osteoporosis International was the most productive journal concerning T2DOP research. National Natural Science Foundation of China was the primary funding source for this research area. "Bone-mineral density", "fracture risk", and "postmenopausal women" were the most high-frequency keywords over the past 10 years. CONCLUSION: This was the first bibliometric study of diabetes mellitus and osteoporosis to exclusively examine type 2 diabetes mellitus. Our findings would provide guidance to understand the research frontiers and hot directions in the near future.

The dual ECL signal enhancement strategy of Pd nanoparticles attached covalent organic frameworks and exonuclease cycling reaction for the ultrasensitive detection of progesterone.

Nowadays, novel and efficient signal amplification strategy in electrochemiluminescence (ECL) platform is urgently needed to enhance the sensitivity of biosensor. In this work, the dual ECL signal enhancement strategy was constructed by the interactions of Pd nanoparticles attached covalent organic frameworks (Pd NPs@COFs) with tris (bipyridine) ruthenium (RuP) and Exonuclease III (Exo.III) cycle reaction. Within this strategy, the COFs composite was generated from the covalent reaction between 2-nitro-1,4-phenylenediamine (NPD) and trialdehyde phloroglucinol (Tp), and then animated by glutamate (Glu) to attach the Pd NPs. Next, the "signal on" ECL biosensor was constructed by the coordination assembly of thiolation capture DNA (cDNA) onto the Pd NPs@COFs modified electrode. After the aptamer recognition of progesterone (P4) with hairpin DNA 1 (HP1), the Exo. III cycle reaction was initiated with HP2 to generate free DNA, which hybridized with cDNA to form double-stranded DNA (dsDNA). For that, the RuP was embedded into the groove of dsDNA and achieved the ultrasensitive detection of P4 with a lower limit of detection (LOD) down to 0.45 pM, as well as the excellent selectivity and stability. This work expands the COFs-based materials application in ECL signal amplification and valuable DNA cyclic reaction in biochemical testing field.

GATA3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in breast cancer.

BACKGROUND: Inadequate DNA damage repair promotes aberrant differentiation of mammary epithelial cells. Mammary luminal cell fate is mainly determined by a few transcription factors including GATA3. We previously reported that GATA3 functions downstream of BRCA1 to suppress aberrant differentiation in breast cancer. How GATA3 impacts DNA damage repair preventing aberrant cell differentiation in breast cancer remains elusive. We previously demonstrated that loss of p18, a cell cycle inhibitor, in mice induces luminal-type mammary tumors, whereas depletion of either Brca1 or Gata3 in p18 null mice leads to basal-like breast cancers (BLBCs) with activation of epithelial-mesenchymal transition (EMT). We took advantage of these mutant mice to examine the role of Gata3 as well as the interaction of Gata3 and Brca1 in DNA damage repair in mammary tumorigenesis. RESULTS: Depletion of Gata3, like that of Brca1, promoted DNA damage accumulation in breast cancer cells in vitro and in basal-like breast cancers in vivo. Reconstitution of Gata3 improved DNA damage repair in Brca1-deficient mammary tumorigenesis. Overexpression of GATA3 promoted homologous recombination (HR)-mediated DNA damage repair and restored HR efficiency of BRCA1-deficient cells. Depletion of Gata3 sensitized tumor cells to PARP inhibitor (PARPi), and reconstitution of Gata3 enhanced resistance of Brca1-deficient tumor cells to PARP inhibitor. CONCLUSIONS: These results demonstrate that Gata3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in mammary tumorigenesis and progression. Our findings suggest that PARP inhibitors are effective for the treatment of GATA3-deficient BLBCs.

Prediction model for hepatitis B e antigen seroconversion in chronic hepatitis B with peginterferon-alfa treated based on a response-guided therapy strategy.

BACKGROUND: Models for predicting hepatitis B e antigen (HBeAg) seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) after nucleos(t)ide analog treatment are rare. AIM: To establish a simple scoring model based on a response-guided therapy (RGT) strategy for predicting HBeAg seroconversion and hepatitis B surface antigen (HBsAg) clearance. METHODS: In this study, 75 previously treated patients with HBeAg-positive CHB underwent a 52-week peginterferon-alfa (PEG-IFNα) treatment and a 24-wk follow-up. Logistic regression analysis was used to assess parameters at baseline, week 12, and week 24 to predict HBeAg seroconversion at 24 wk post-treatment. The two best predictors at each time point were used to establish a prediction model for PEG-IFNα therapy efficacy. Parameters at each time point that met the corresponding optimal cutoff thresholds were scored as 1 or 0. RESULTS: The two most meaningful predictors were HBsAg ≤ 1000 IU/mL and HBeAg ≤ 3 S/CO at baseline, HBsAg ≤ 600 IU/mL and HBeAg ≤ 3 S/CO at week 12, and HBsAg ≤ 300 IU/mL and HBeAg ≤ 2 S/CO at week 24. With a total score of 0 vs 2 at baseline, week 12, and week 24, the response rates were 23.8%, 15.2%, and 11.1% vs 81.8%, 80.0%, and 82.4%, respectively, and the HBsAg clearance rates were 2.4%, 3.0%, and 0.0%, vs 54.5%, 40.0%, and 41.2%, respectively. CONCLUSION: We successfully established a predictive model and diagnosis-treatment process using the RGT strategy to predict HBeAg and HBsAg seroconversion in patients with HBeAg-positive CHB undergoing PEG-IFNα therapy.

Investigation of peri-implant diseases prevalence and related risk indicators in patients with treated severe periodontitis over 4 years after restoration.

Background/purpose: History of periodontitis is a well-documented risk indicator of peri-implantitis. However, the influence of severity of periodontitis is still unclear, especially for severe periodontitis. This study was aimed to investigate the prevalence of peri-implant disease and analyze the risk indicators in patients with treated severe periodontitis. Materials and methods: A total of 182 implants from 88 patients (44 males and 44 females) with severe periodontitis with a mean fellow-up period of 76.5 months were enrolled in this study. Patient and implant information, and periodontal and peri-implant conditions were collected to evaluate the prevalence of peri-implant disease and risk indicators. Results: The prevalence of peri-implantitis was 9.1% and 6.6% at the patient-level and implant-level. The prevalence of peri-implant mucositis was 76.1% and 51.1% at the patient-level and implant-level. Risk indicators of peri-implantitis included older age (OR: 1.132), poor proximal cleaning habits (OR: 14.218), implants in anterior area (OR: 10.36), poor periodontal disease control (OR: 12.76), high peri-implant plaque index (OR: 4.27), and keratinized tissue width (KTW)＜2 mm (OR: 19.203). Conclusion: Implants in patients with severe periodontitis after periodontal treatment and maintenance show a low prevalence (9.1%) of peri-implantitis and a relatively high prevalence (76.2%) of peri-implant mucositis. Patient age, peri-implant proximal cleaning habits, implant position, periodontal disease control, peri-implant plaque index, and KTW are associated with prevalence of peri-implantitis.

[Correlation between femoral offset, rotation center and leg length discrepancy after total hip arthroplasty based on digital analysis].

OBJECTIVE: CT scans combined with Mimics software were used to measure femoral offset (FO), rotation center height (RCH) and lower leg length discrepancy (LLD) following total hip arthroplasty (THA), and the relationship between FO, RCH and LLD after THA is discussed. METHODS: Retrospective analysis was performed on 40 patients with unilateral THA who met standard cases from October 2020 to June 2022. There were 21 males and 19 females, 18 patients on the left side and 22 patients on the right side, aged range from 30 to 81 years old, with an average age of (58.90 ±14.13) years old, BMI ranged from 17.3 to 31.5 kg·m-2 with an average of (25.3±3.4) kg·m-2. There were 30 cases of femoral head necrosis (Ficat type Ⅳ), 2 cases of hip osteoarthritis (Tönnis type Ⅲ), 2 cases of developmental hip dislocation combined with end-stage osteoarthritis (Crowe type Ⅲ), and 6 cases of femoral neck fracture (Garden type Ⅳ). Three-dimensional CT reconstruction of pelvis was taken preoperative and postoperative, and three-dimensional reconstruction model was established after processing by Mimics software. FO, RCH and LLD were measured on the model. The criteria for FO reconstruction were as follows:postoperative bilateral FO difference less than 5 mm;the standard for equal length of both lower limbs was as follows:postoperative LLD difference less than 5 mm. RESULTS: Bilateral FO difference was positively correlated with LLD (r=0.744, P<0.001). Chi-square test was performed between the FO reconstructed group and the non-reconstructed eccentricity group:The results showed that the isometric ratio of lower limbs in the FO reconstructed group was significantly higher than that in the FO reconstructed group (χ2=6.320, P=0.012). The bilateral RCH difference was significantly negatively correlated with LLD(r=-0.877, P<0.001). There is a linear relationship between bilateral FO difference and bilateral RCH difference and postoperative LLD, and the linear regression equation is satisfied:postoperative LLD=0.038x-0.099y+0.257(x:postoperative bilateral FO difference, y:postoperative bilateral RCH difference; Unit:cm), F=77.993, R2=0.808, P=0.009. CONCLUSION: After THA, LLD increased with the increase of FO and decreased with the increase of RCH. The effect of lower limb isometric length can be obtained more easily by reconstruction of FO. There is a linear relationship between the bilateral FO difference and the bilateral RCH difference after THA and LLD, and the regression equation can provide a theoretical reference for judging LLD.

BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks.

Reprogramming to pluripotency is associated with DNA damage and requires the functions of the BRCA1 tumor suppressor. Here, we leverage separation-of-function mutations in BRCA1/2 as well as the physical and/or genetic interactions between BRCA1 and its associated repair proteins to ascertain the relevance of homology-directed repair (HDR), stalled fork protection (SFP), and replication gap suppression (RGS) in somatic cell reprogramming. Surprisingly, loss of SFP and RGS is inconsequential for the transition to pluripotency. In contrast, cells deficient in HDR, but proficient in SFP and RGS, reprogram with reduced efficiency. Conversely, the restoration of HDR function through inactivation of 53bp1 rescues reprogramming in Brca1-deficient cells, and 53bp1 loss leads to elevated HDR and enhanced reprogramming in mouse and human cells. These results demonstrate that somatic cell reprogramming is especially dependent on repair of replication-associated double-strand breaks (DSBs) by the HDR activity of BRCA1 and BRCA2 and can be improved in the absence of 53BP1.

Suppression of the METTL3-m6A-integrin ß1 axis by extracellular acidification impairs T cell infiltration and antitumor activity.

The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the "tumor acidity (TuAci) score" for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin ß1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.