A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Revealing intact neuronal circuitry in centimeter-sized formalin-fixed paraffin-embedded brain.

Tissue-clearing and labeling techniques have revolutionized brain-wide imaging and analysis, yet their application to clinical formalin-fixed paraffin-embedded (FFPE) blocks remains challenging. We introduce HIF-Clear, a novel method for efficiently clearing and labeling centimeter-thick FFPE specimens using elevated temperature and concentrated detergents. HIF-Clear with multi-round immunolabeling reveals neuron circuitry regulating multiple neurotransmitter systems in a whole FFPE mouse brain and is able to be used as the evaluation of disease treatment efficiency. HIF-Clear also supports expansion microscopy and can be performed on a non-sectioned 15-year-old FFPE specimen, as well as a 3-month formalin-fixed mouse brain. Thus, HIF-Clear represents a feasible approach for researching archived FFPE specimens for future neuroscientific and 3D neuropathological analyses.

PEGylated chitosan-coated nanophotosensitizers for effective cancer treatment by photothermal-photodynamic therapy combined with glutathione depletion.

The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. However, the poor photostability and photothermal conversion efficiency (PCE) of organic small-molecule photosensitizers, and the intracellular glutathione (GSH)-mediated singlet oxygen scavenging largely decline the antitumor efficacy of PTT and PDT. Herein, a versatile nanophotosensitizer (NPS) system is developed by ingenious incorporation of indocyanine green (ICG) into the PEGylated chitosan (PEG-CS)-coated polydopamine (PDA) nanoparticles via multiple π-π stacking, hydrophobic and electrostatic interactions. The PEG-CS-covered NPS showed prominent colloidal and photothermal stability as well as high PCE (ca 62.8 %). Meanwhile, the Michael addition between NPS and GSH can consume GSH, thus reducing the GSH-induced singlet oxygen scavenging. After being internalized by CT26 cells, the NPS under near-infrared laser irradiation produced massive singlet oxygen with the aid of thermo-enhanced intracellular GSH depletion to elicit mitochondrial damage and lipid peroxide formation, thus leading to ferroptosis and apoptosis. Importantly, the combined PTT and PDT delivered by NPS effectively inhibited CT26 tumor growth in vivo by light-activated intense hyperthermia and redox homeostasis disturbance. Overall, this work presents a new tactic of boosting antitumor potency of ICG-mediated phototherapy by PEG-CS-covered NPS.

Efficacy and immunogenicity of AS04-HPV-16/18 vaccine in females with existing cervical HR-HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide.

Females with existing high-risk HPV (HR-HPV) infections remain at risk of subsequent multiple or recurrent infections, on which benefit from HPV vaccines was under-reported. We pooled individual-level data from four large-scale, RCTs of AS04-HPV-16/18 vaccine to evaluate efficacy and immunogenicity in females DNA-positive to any HR-HPV types at first vaccination. Females receiving the AS04-HPV-16/18 vaccine in the original RCTs constituted the vaccine group in the present study, while those unvaccinated served as the control group. Vaccine efficacy (VE) against new infections and associated cervical intraepithelial neoplasia (CIN) 2+ in females DNA-negative to the considered HR-HPV type but positive to any other HR-HPV types, VE against reinfections in females DNA-positive to the considered HR-HPV type but cleared naturally during later follow-up, and levels of anti-HPV-16/18 IgG were assessed. Our final analyses included 5137 females (vaccine group = 2532, control group = 2605). The median follow-up time was 47.88 months (IQR: 45.72-50.04). For the prevention of precancerous lesions related to the non-infected HR-HPV types at baseline, VE against HPV-16/18 related CIN 2+ was 82.70% (95% CI: 63.70-93.00%). For the prevention of reinfections related to the infected HR-HPV types following natural clearance, VE against HPV-16/18 12MPI was non-significant (p > .05), albeit robust immunity persisted for at least 48 months. Females with existing HR-HPV infections at first vaccination still benefit from vaccination in preventing precancers related to the non-infected types at baseline. VE against reinfections related to the infected types following natural clearance remains to be further investigated.

Tumor-activated targetable photothermal chemotherapy using IR780/zoledronic acid-containing hybrid polymeric nanoassemblies with folate modification to treat aggressive breast cancer.

To effectively treat aggressive breast cancer by tumor-activated targetable photothermal chemotherapy, in this work, folate (FA)-modified hybrid polymeric nanoassemblies (HPNs) with a poly(ethylene glycol) (PEG)-detachable capability are developed as vehicles for tumor-targeted co-delivery of IR780, a lipophilic photothermal reagent, and zoledronic acid (ZA), a hydrophilic chemotherapy drug. Through hydrophobic interaction-induced co-assembly, IR780 molecules and ZA/poly(ethylenimine) (PEI) complexes were co-encapsulated into a poly(lactic-co-glycolic acid) (PLGA)-rich core stabilized by the amphiphilic FA-modified D-α-tocopheryl poly(ethylene glycol) succinate (FA-TPGS) and acidity-sensitive PEG-benzoic imine-octadecane (C18) (PEG-b-C18) conjugates. The developed FA-ZA/IR780@HPNs with high ZA and IR780 payloads not only showed excellent colloidal stability in a serum-containing milieu, but also promoted IR780-based photostability and photothermal conversion efficiency. Furthermore, for FA-ZA/IR780@HPNs under simulated physiological conditions, the premature leakage of IR780 and ZA molecules was remarkably declined. In a mimetic acidic tumor microenvironment, the uptake of FA-ZA/IR780@HPNs by FA receptor-overexpressed 4T1 breast cancer cells was remarkably promoted by PEG detachment combined with FA receptor-mediated endocytosis, thus effectively hindering migration of cancer cells and augmenting the anticancer efficacy of photothermal chemotherapy. Notably, the in vivo studies demonstrated that the FA-ZA/IR780@HPNs largely deposited at 4T1 tumor sites and profoundly suppressed tumor growth and metastasis without severe systemic toxicity upon near infrared (NIR)-triggered IR780-mediated hyperthermia integrated with ZA chemotherapy. This work presents a practical strategy to treat aggressive breast tumors with tumor-triggered targetable photothermal chemotherapy using FA-ZA/IR780@HPNs.

Lung metastasis-Harnessed in-Situ adherent porous organic nanosponge-mediated antigen capture for A self-cascaded detained dendritic cells and T cell infiltration.

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.

In Situ Forming of Nitric Oxide and Electric Stimulus for Nerve Therapy by Wireless Chargeable Gold Yarn-Dynamos.

Endogenous signals, namely nitric oxide (NO) and electrons, play a crucial role in regulating cell fate as well as the vascular and neuronal systems. Unfortunately, utilizing NO and electrical stimulation in clinical settings can be challenging due to NO's short half-life and the invasive electrodes required for electrical stimulation. Additionally, there is a lack of tools to spatiotemporally control gas release and electrical stimulation. To address these issues, an "electromagnetic messenger" approach that employs on-demand high-frequency magnetic field (HFMF) to trigger NO release and electrical stimulation for restoring brain function in cases of traumatic brain injury is introduced. The system comprises a NO donor (poly(S-nitrosoglutathione), pGSNO)-conjugated on a gold yarn-dynamos (GY) and embedded in an implantable silk in a microneedle. When subjected to HFMF, conductive GY induces eddy currents that stimulate the release of NO from pGSNO. This process significantly enhances neural stem cell (NSC) synapses' differentiation and growth. The combined strategy of using NO and electrical stimulation to inhibit inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury is demonstrated in vivo.

Tackling barriers to scale up human papillomavirus vaccination in China: progress and the way forward.

The human papillomavirus (HPV) vaccine is the first vaccine developed specifically targeting the prevention of cervical cancer. For more than 15 years, China has expedited a series of efforts on research and development of the domestically manufactured HPV vaccines, producing local population-based evidence, promoting free HPV vaccination from pilots, and launching action plans to tackle barriers in the scale-up of HPV vaccination. To further roll out the HPV vaccination program in China, several challenges should be addressed to support the steps forward. The availability of more locally manufactured HPV vaccines, pricing negotiation and local evidence supporting the efficacy of one-dose schedule would greatly alleviate the continued supply and financial constraints in China. Meanwhile, more attention should be paid to girls living in low-resource areas and males to ensure equal access to the HPV vaccination. Furthermore, linkage to secondary prevention and further real-world monitoring and evaluation are warranted to inform effective cervical cancer prevention strategies in the post-vaccine era.

Sustained Release of Nitric Oxide-Mediated Angiogenesis and Nerve Repair by Mussel-Inspired Adaptable Microreservoirs for Brain Traumatic Injury Therapy.

Traumatic brain injury (TBI) triggers inflammatory response and glial scarring, thus substantially hindering brain tissue repair. This process is exacerbated by the accumulation of activated immunocytes at the injury site, which contributes to scar formation and impedes tissue repair. In this study, a mussel-inspired nitric oxide-release microreservoir (MINOR) that combines the features of reactive oxygen species (ROS) scavengers and sustained NO release to promote angiogenesis and neurogenesis is developed for TBI therapy. The injectable MINOR fabricated using a microfluidic device exhibits excellent monodispersity and gel-like self-healing properties, thus allowing the maintenance of its structural integrity and functionality upon injection. Furthermore, polydopamine in the MINOR enhances cell adhesion, significantly reduces ROS levels, and suppresses inflammation. Moreover, a nitric oxide (NO) donor embedded into the MINOR enables the sustained release of NO, thus facilitating angiogenesis and mitigating inflammatory responses. By harnessing these synergistic effects, the biocompatible MINOR demonstrates remarkable efficacy in enhancing recovery in mice. These findings benefit future therapeutic interventions for patients with TBI.

The Diagnostic and Prognostic Value of EBUS-TBNA for Intrathoracic Metastasis in Previously Treated Patients With Head and Neck Cancer.

OBJECTIVE: The present study assessed the diagnostic and prognostic significance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for suspected intrathoracic metastasis after HNC treatment. METHODS: A retrospective analysis was conducted on 75 patients with a prior history of head and neck cancer treatment who underwent EBUS-TBNA for suspected intrathoracic metastases between March 2012 and December 2021. RESULTS: A total of 126 targeted lesions, including 107 mediastinal/hilar lymph nodes and 19 intrapulmonary/mediastinal masses, were sampled. The metastatic head and neck cancer (HNC) cases detected by EBUS-TBNA consisted of nasopharyngeal carcinoma (n = 24), oropharyngeal carcinoma (n = 3), hypopharynx carcinoma (n = 6), laryngeal carcinoma (n = 6), and oral cavity carcinoma (n = 6). Cases with negative EBUS-TBNA results consisted of tuberculosis (n = 9), sarcoidosis (n = 3), anthracosis (n = 9), and reactive lymphadenitis (n = 9). Six false-negative cases were found among the 75 patients with suspected intrathoracic metastases. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the EBUS-TBNA procedure for metastatic HNC were 88.2, 100.0, 100.0, 80, and 92.0%, respectively. The diagnosis of HNC intrathoracic metastasis by EBUS-TBNA correlated with an adverse prognosis in terms of overall survival (OS) (P = .008). The log-rank univariate analysis and Cox regression multivariate analysis results indicated that the detection of metastatic HNC through EBUS-TBNA was a significant independent prognostic factor for patients with HNC who had received prior treatment. CONCLUSIONS: Endobronchial ultrasound-guided transbronchial needle aspiration is a safe, effective, and minimally invasive procedure for assessing suspected intrathoracic metastasis in HNC patients after treatment. The intrathoracic metastasis detected by EBUS-TBNA has crucial prognostic significance in previously treated HNC patients.

Programmed T cells infiltration into lung metastases with harnessing dendritic cells in cancer immunotherapies by catalytic antigen-capture sponges.

T lymphocytes served as immune surveillance to suppress metastases by physically interacting with cancer cells. Whereas tumor immune privilege and heterogeneity protect immune attack, it limits immune cell infiltration into tumors, especially in invasive metastatic clusters. Here, a catalytic antigen-capture sponge (CAS) containing the catechol-functionalized copper-based metal organic framework (MOF) and chloroquine (CQ) for programming T cells infiltration is reported. The intravenously injected CAS accumulates at the tumor via the folic acid-mediated target and margination effect. In metastases, Fenton-like reaction induced by copper ions of CAS disrupts the intracellular redox potential, i.e., chemodynamic therapy (CDT), thereby reducing glutathione (GSH) levels. Furthermore, CQ helps inhibit autophagy by inducing lysosomal deacidification during CDT. This process leads to the breakdown of self-defense mechanisms, which exacerbates cytotoxicity. The therapies promote the liberation of tumor-associated antigens, such as neoantigens and damage-associated molecular patterns (DAMPs). Subsequently, the catechol groups present on CAS perform as antigen reservoirs and transport the autologous tumor-associated antigens to dendritic cells, resulting in prolonged immune activation. The CAS, which is capable of forming in-situ, serves as an antigen reservoir in CDT-mediated lung metastasis and leads to the accumulation of immune cells in metastatic clusters, thus hindering metastatic tumors.

Programmed antigen capture-harnessed dendritic cells by margination-hitchhiking lung delivery.

Adoptive T cells and immunotherapy suppress the most destructive metastatic tumors and prevent tumor recurrence by inducing T lymphocytes. However, the heterogeneity and immune privilege of invasive metastatic clusters often reduce immune cell infiltration and therapeutic efficacy. Here, the red blood cells (RBC)-hitchhiking mediated lung metastasis delivery of multi-grained iron oxide nanostructures (MIO) programming the antigen capture, dendritic cell harnessing, and T cell recruitment is developed. MIO is assembled to the surface of RBCs by osmotic shock-mediated fusion, and reversible interactions enable the transfer of MIO to pulmonary capillary endothelial cells by intravenous injection by squeezing RBCs at the pulmonary microvessels. RBC-hitchhiking delivery revealed that >65% of MIOs co-localized in tumors rather than normal tissues. In alternating magnetic field (AMF)-mediated magnetic lysis, MIO leads to the release of tumor-associated antigens, namely neoantigens and damage-associated molecular patterns. It also acted as an antigen capture agent-harnessed dendritic cells delivers these antigens to lymph nodes. By utilizing site-specific targeting, erythrocyte hitchhiker-mediated delivery of MIO to lung metastases improves survival and immune responses in mice with metastatic lung tumors.

Cost-effectiveness of the screen-and-treat strategies using HPV test linked to thermal ablation for cervical cancer prevention in China: a modeling study.

BACKGROUND: Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. METHODS: We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. RESULTS: Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (-$818,430 to -$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). CONCLUSIONS: Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

Clinical performance of a newly developed domestic urine-based HPV test for cervical cancer screening in China.

Although urine-based human papillomavirus (HPV) detection is promising in cervical cancer screening, it has not yet been well-developed. Women aged 30-65 were invited to participate in the current study to provide one urine and two paired vaginal samples. Urine was detected by polymerase chain reaction (PCR)-based HPV test (urine-based HPV test). Two vaginal samples were tested by careHPV and GenPlex® HPV genotyping assay, respectively. Women with vaginal HPV positive were called back for colposcopy and biopsied if clinically indicated. The consistency was 79.0% (κ = 0.563) and 80.5% (κ = 0.605) between the urine-based HPV test, careHPV test, and GenPlex® HPV genotyping assay. Against CIN2 detection, the careHPV test showed 77.4% sensitivity, and 71.0% specificity, while the GenPlex® HPV genotyping assay had a sensitivity of 100% and a specificity of 58.7%. For urine-based HPV test, the corresponding rates were 96.8% and 58.7%. Moreover, no significant differences were observed between the urine-based HPV test and careHPV test (p = 0.3395) and GenPlex® HPV genotyping assay (p = 0.338). The newly developed urine-based HPV test demonstrated acceptable consistency and comparable clinical performance with referenced HPV tests for vaginal samples. Therefore, urine-based HPV detection could be a useful alternative for women with difficulties to access cervical cancer screening.

Implementation of visual inspection with acetic acid and Lugol's iodine for cervical cancer screening in rural China.

OBJECTIVE: To address the value of visual inspection where HPV-based screening is not yet available, we evaluated the real-world effectiveness of visual inspection with acetic acid (VIA) and with Lugol's iodine (VILI) as a primary screening method for cervical cancer in rural China. METHODS: A total of 206 133 women aged 30-59 years received two rounds of VIA/VILI screening for cervical cancer in 2006-2010. Women with positive screening results underwent colposcopy and direct biopsy, and were treated if cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was diagnosed. Clinical effectiveness of VIA/VILI was evaluated by process and outcome measures. RESULTS: The VIA/VILI positivity rate, biopsy rate and detection rate of CIN2+ in the second round were significantly lower than in the first round. The 2-year cumulative detection rate of CIN2+ varied from 0.53% to 0.90% among the four cohorts initiated in 2006, 2007, 2008, and 2009. The first round of screening detected 60%-83% of CIN2, 70%-86% of CIN3, and 88%-100% of cervical cancer. Over 92% of CIN2+ were found at the early stage. CONCLUSION: Multiple rounds of visual inspection with continuous training and quality assurance could act as a temporary substitutional screening method for cervical cancer in resource-restricted settings.

Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks.

Traumatic brain injury causes inflammation and glial scarring that impede brain tissue repair, so stimulating angiogenesis and recovery of brain function remain challenging. Here we present an adaptable conductive microporous hydrogel consisting of gold nanoyarn balls-coated injectable building blocks possessing interconnected pores to improve angiogenesis and recovery of brain function in traumatic brain injury. We show that following minimally invasive implantation, the adaptable hydrogel is able to fill defects with complex shapes and regulate the traumatic brain injury environment in a mouse model. We find that placement of this injectable hydrogel at peri-trauma regions enhances mature brain-derived neurotrophic factor by 180% and improves angiogenesis by 250% in vivo within 2 weeks after electromagnetized stimulation, and that these effects facilitate neuron survival and motor function recovery by 50%. We use blood oxygenation level-dependent functional neuroimaging to reveal the successful restoration of functional brain connectivity in the corticostriatal and corticolimbic circuits.

Performance of Cervical Screening a Decade Following HPV Vaccination: The Costa Rica Vaccine Trial.

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

Programmed Catalytic Therapy-Mediated ROS Generation and T-Cell Infiltration in Lung Metastasis by a Dual Metal-Organic Framework (MOF) Nanoagent.

Nano-catalytic agents actuating Fenton-like reaction in cancer cells cause intratumoral generation of reactive oxygen species (ROS), allowing the potential for immune therapy of tumor metastasis via the recognition of tumor-associated antigens. However, the self-defense mechanism of cancer cells, known as autophagy, and unsustained ROS generation often restricts efficiency, lowering the immune attack, especially in invading metastatic clusters. Here, a functional core-shell metal-organic framework nanocube (dual MOF) doubling as a catalytic agent and T cell infiltration inducer that programs ROS and inhibits autophagy is reported. The dual MOF integrated a Prussian blue (PB)-coated iron (Fe2+)-containing metal-organic framework (MOF, MIL88) as a programmed peroxide mimic in the cancer cells, facilitating the sustained ROS generation. With the assistance of Chloroquine (CQ), the inhibition of autophagy through lysosomal deacidification breaks off the self-defense mechanism and further improves the cytotoxicity. The purpose of this material design was to inhibit autophagy and ROS efficacy of the tumor, and eventually improve T cell recruitment for immune therapy of lung metastasis. The margination and internalization-mediated cancer cell uptake improve the accumulation of dual MOF of metastatic tumors in vivo. The effective catalytic dual MOF integrated dysfunctional autophagy at the metastasis elicits the ~3-fold recruitment of T lymphocytes. Such synergy of T cell recruitment and ROS generation transported by dual MOF during the metastases successfully suppresses more than 90% of tumor foci in the lung.

Rabies Virus Glycoprotein-Mediated Transportation and T Cell Infiltration to Brain Tumor by Magnetoelectric Gold Yarnballs.

T lymphocyte infiltration with immunotherapy potentially suppresses most devastating brain tumors. However, local immune privilege and tumor heterogeneity usually limit the penetration of immune cells and therapeutic agents into brain tumors, leading to tumor recurrence after treatment. Here, a rabies virus glycoprotein (RVG)-camouflaged gold yarnball (RVG@GY) that can boost the targeting efficiency at a brain tumor via dual hierarchy- and RVG-mediated spinal cord transportation, facilitating the decrease of tumor heterogeneity for T cell infiltration, is developed. Upon magnetoelectric irradiation, the electron current generated on the GYs activates the electrolytic penetration of palbociclib-loaded dendrimer (Den[Pb]) deep into tumors. In addition, the high-density GYs at brain tumors also induces the disruption of cell-cell interactions and T cell infiltration. The integration of the electrolytic effects and T cell infiltration promoted by drug-loaded RVG@GYs deep in the brain tumor elicits sufficient T cell numbers and effectively prolongs the survival rate of mice with orthotopic brain tumors.