Phase-locked µPIV analysis of flow dynamics in a simulated root canal with different laser-activated irrigations.

PURPOSE: To measure the dynamic characteristics of the flow field in a complex root canal model activated by two laser-activated irrigation (LAI) modalities at different activation energy outputs: photon-induced photoacoustic streaming (PIPS) and microshort pulse (MSP). METHODS: A phase-locked micro-scale Particle Image Velocimetry (µPIV) system was employed to characterise the temporal variations of LAI-induced velocity fields in the root canal following a single laser pulse. The wall shear stress (WSS) in the lateral root canal was subsequently estimated from the phase-averaged velocity fields. RESULTS: Both PIPS and MSP were able to generate the 'breath mode' of the irrigant current under all tested conditions. The transient irrigation flush in the root canal peaked at speeds close to 6 m/s. However, this intense flushing effect persisted for only about 2000 µs (or 3% of a single laser-pulse activation cycle). For MSP, the maximum WSS magnitude was approximately 3.08 Pa at an activation energy of E = 20 mJ/pulse, rising to 9.01 Pa at E = 50 mJ/pulse. In comparison, PIPS elevated the WSS to 10.63 Pa at E = 20 mJ/pulse. CONCLUSION: Elevating the activation energy can boost the peak flushing velocity and the maximum WSS, thereby enhancing irrigation efficiency. Given the same activation energy, PIPS outperforms MSP. Additionally, increasing the activation frequency may be an effective strategy to improve irrigation performance further.

Study on the Performance of a Surface with Coupled Wettability Difference and Convex-Stripe Array for Improved Air Layer Stability.

The existence of an air layer reduces friction drag on superhydrophobic surfaces. Therefore, improving the air layer stability of superhydrophobic surfaces holds immense significance in reducing both energy consumption and environmental pollution caused by friction drag. Based on the properties of mathematical discretization and the contact angle hysteresis generated by the wettability difference, a surface coupled with a wettability difference treatment and a convex-stripe array is developed by laser engraving and fluorine modification, and its performance in improving the air layer stability is experimentally studied in a von Kármán swirling flow field. The results show that the destabilization of the air layer is mainly caused by the Kelvin-Helmholtz instability, which is triggered by the density difference between gas and liquid, as well as the tangential velocity difference between gas and liquid. When the air layer is relatively thin, tangential wave destabilization occurs, whereas for larger thicknesses, the destabilization mode is coupled wave destabilization. The maximum Reynolds number that keeps the air layer fully covering the surface of the rotating disk (with drag reduction performance) during the disk rotation process is defined as the critical Reynolds number (Rec), which is 1.62 × 105 for the uniform superhydrophobic surface and 3.24 × 105 for the superhydrophobic surface with a convex stripe on the outermost ring (SCSSP). Individual treatments of wettability difference and a convex-stripe array on the SCSSP further improve the air layer stability, but Rec remains at 3.24 × 105. Finally, the coupling of the wettability difference treatment with a convex-stripe array significantly improves the air layer stability, resulting in an increase of Rec to 4.05 × 105, and the drag reduction rate stably maintained around 30%.

Unlocking the potential of organoids in cancer treatment and translational research: An application of cytologic techniques.

Patient-derived organoid models hold promise for advancing clinical cancer research, including diagnosis and personalized and precision medicine approaches, and cytology, in particular, plays a pivotal role in this process. These three-dimensional multicellular structures are heterogeneous, potentially maintain the cancer phenotype, and conserve the genomic, transcriptomic, and epigenomic patterns of the parental tumors. To ensure that only tumor tissue is used for organoid development, cytologic validation is necessary before initiating the process of organoid generation. Here, we explore the technology of tumor organoids and discuss the fundamental application of cytology as a simple and cost-effective approach toward organoid development. We also underscore the potential application of organoid development in drug efficacy studies for lung cancer and head and neck tumors. Additionally, we stress the importance of using fine-needle aspiration to generate tumoroids.

Acute 1,2-Dichloropropane Poisoning due to Ingestion of Rubber Cement: An Autopsy Case Report and Review.

ABSTRACT: 1,2-Dichloropropane (1,2-DCP) is a common industrial solvent and chemical intermediate that can cause acute poisoning to humans through exposure during its production and industrial use. The target organs of 1,2-DCP include the eyes, respiratory system, liver, kidney, central nervous system, and skin. Forensic identification of 1,2-DCP poisoning is difficult because of the lack of characteristic pathological changes. This article reports an autopsy case of acute 1,2-DCP poisoning caused by self-ingestion of rubber cement. A woman developed seizures and coagulation dysfunction after ingesting approximately 10 mL of rubber cement and died 43 hours later. Autopsy revealed generalized subcutaneous hemorrhage, cardiopulmonary multifocal hemorrhage, bronchopneumonia, severe cerebral edema, focal hepatic necrosis, granular deposition in the glomerular capsule and renal tubules, and delipidation of the adrenal cortex. These findings indicate that 1,2-DCP poisoning can induce central nervous system dysfunction, respiratory system damage, liver and kidney function damage, hemolytic anemia, disseminated intravascular coagulation, and adrenal damage. This case may provide useful perspectives for forensic identification of 1,2-DCP poisoning in the future.

Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer.

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-ß1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

Unified discontinuous Galerkin finite-element framework for transient conjugated radiation-conduction heat transfer.

Research on conjugated radiation-conduction (CRC) heat transfer in participating media is of vital scientific and engineering significance due to its extensive applications. Appropriate and practical numerical methods are essential to forecast the temperature distributions during the CRC heat-transfer processes. Here, we established a unified discontinuous Galerkin finite-element (DGFE) framework for solving transient CRC heat-transfer problems in participating media. To overcome the mismatch between the second-order derivative in the energy balance equation (EBE) and the DGFE solution domain, we rewrite the second-order EBE as two first-order equations and then solve both the radiative transfer equation (RTE) and the EBE in the same solution domain, resulting in the unified framework. Comparisons between the DGFE solutions with published data confirm the accuracy of the present framework for transient CRC heat transfer in one- and two-dimensional media. The proposed framework is further extended to CRC heat transfer in two-dimensional anisotropic scattering media. Results indicate that the present DGFE can precisely capture the temperature distribution at high computational efficiency, paving the way for a benchmark numerical tool for CRC heat-transfer problems.

Transient apical peak pressure measurement of Er:YAG laser-activated irrigation in different in vitro tooth models using a high-frequency sensor system.

The transient apical pressure side effect is an important safety consideration for Er:YAG laser-activated irrigation (LAI). Therefore, this study aimed to measure the transient apical peak pressure (TAPP) of LAI under different laser settings in various tooth models using a high-frequency sensor system. Tooth models with different pulp chamber structures, apical diameters, and curvatures were prepared using transparent resin and filled with deionised water. The Er:YAG laser fibre was placed 3 mm from the root canal orifice. Irrigation was performed at 10-40 mJ and 20-50 Hz using the super short pulse mode. The TAPP was measured using a 50,000-sample/second pressure sensor connected to the models' apices. The TAPP of LAI was significantly higher than that of other chemical preparation methods. Among all investigated factors, pulp chamber anatomy and apical diameters had the greatest effects and were highly related to the apical peak pressure. Root canal curvature showed no direct correlation with TAPP. The larger the final prepared working width, the greater the TAPP. Furthermore, both pulse energy and frequency had positive correlations with TAPP. In conclusion, tooth anatomy factors and laser parameter settings influenced TAPP during Er:YAG LAI. Therefore, proper settings of laser parameters are important to improve the safety of Er:YAG LAI.

A transformable nanoplatform with multiple therapeutic and immunostimulatory properties for treatment of advanced cancers.

Cancer is a complex pathological phenomenon that needs to be treated from different aspects. Herein, we developed a size/charge dually transformable nanoplatform (PDR NP) with multiple therapeutic and immunostimulatory properties to effectively treat advanced cancers. The PDR NPs exhibit three different therapeutic modalities (chemotherapy, phototherapy and immunotherapy) that can be used to effectively treat primary and distant tumors, and reduce recurrent tumors; the immunotherapy is simultaneously activated by three major pathways, including toll-like receptor, stimulator of interferon genes and immunogenic cell death, effectively suppresses the tumor development in combination with an immune checkpoint inhibitor. In addition, PDR NPs show size and charge responsive transformability in the tumor microenvironment, which overcomes various biological barriers and efficiently delivers the payloads into tumor cells. Taking these unique characteristics together, PDR NPs effectively ablate primary tumors, activate strong anti-tumor immunity to suppress distant tumors and reduce tumor recurrence in bladder tumor-bearing mice. Our versatile nanoplatform shows great potential for multimodal treatments against metastatic cancers.

Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens.

BACKGROUND: Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle. The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms. There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens. METHODS AND RESULTS: Two experiments were conducted. In Exp. 1, Hy-Line Brown laying hens (n = 45) were sampled according the oviposition cycle (at 0, 6, 12, and 18 h post-oviposition, and at the next oviposition, respectively; n = 9 at each time point). Diurnal rhythms of body calcium/phosphorus ingestions and excretions, serum calcium/phosphorus levels, oviduct uterus calcium transporter expressions, and medullary bone (MB) remodeling were illustrated. In Exp. 2, two diets with different phosphorus levels (0.32% and 0.14% non-phytate phosphorus (NPP), respectively) were alternately presented to the laying hens. Briefly, four phosphorus feeding regimens in total (each included 6 replicates of 5 hens): (1) fed 0.32% NPP at both 09:00 and 17:00; (2) fed 0.32% NPP at 09:00 and 0.14% NPP at 17:00; (3) fed 0.14% NPP at 09:00 and 0.32% NPP at 17:00; (4) fed 0.14% NPP at both 09:00 and 17:00. As a result, the regimen fed 0.14% NPP at 09:00 and 0.32% NPP at 17:00, which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp. 1, enhanced (P < 0.05) MB remodeling (indicated by histological images, serum markers and bone mineralization gene expressions), elevated (P < 0.05) oviduct uterus calcium transportation (indicated by transient receptor potential vanilloid 6 protein expression), and subsequently increased (P < 0.05) eggshell thickness, eggshell strength, egg specific gravity and eggshell index in laying hens. CONCLUSIONS: These results underscore the importance of manipulating the sequence of daily phosphorus ingestion, instead of simply controlling dietary phosphate concentrations, in modifying the bone remodeling process. Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.

Increasing cure rates of solid tumors by immune checkpoint inhibitors.

Immunotherapy has become the central pillar of cancer therapy. Immune checkpoint inhibitors (ICIs), a major category of tumor immunotherapy, reactivate preexisting anticancer immunity. Initially, ICIs were approved only for advanced and metastatic cancers in the salvage setting after or concurrent with chemotherapy at a response rate of around 20-30% with a few exceptions. With significant progress over the decade, advances in immunotherapy have led to numerous clinical trials investigating ICIs as neoadjuvant and/or adjuvant therapies for resectable solid tumors. The promising results of these trials have led to the United States Food and Drug Administration (FDA) approvals of ICIs as neoadjuvant or adjuvant therapies for non-small cell lung cancer, melanoma, triple-negative breast cancer, and bladder cancer, and the list continues to grow. This therapy represents a paradigm shift in cancer treatment, as many early-stage cancer patients could be cured with the introduction of immunotherapy in the early stages of cancer. Therefore, this topic became one of the main themes at the 2021 China Cancer Immunotherapy Workshop co-organized by the Chinese American Hematologist and Oncologist Network, the China National Medical Products Administration and the Tsinghua University School of Medicine. This review article summarizes the current landscape of ICI-based immunotherapy, emphasizing the new clinical developments of ICIs as curative neoadjuvant and adjuvant therapies for early-stage disease.

The Impact of Facility Surgical Caseload Volumes on Survival Outcomes in Patients Undergoing Radical Cystectomy.

The role of surgical experience and its impact on the survival requires further investigation. A cohort of patients undergoing radical cystectomy or anterior pelvic exenteration for localized bladder cancer between 2006 and 2013 at 1143 facilities across the United States was identified using the National Cancer Database and analyzed. Using overall survival (OS) as the primary outcome, the relationship between facility annual caseload (FAC) and facility annual surgical caseload (FASC) for those undergoing curative surgery was examined. Four volume groups (VG) depending on caseload using both FAC and FASC were defined. These included VG1: below 50th percentile, VG2: 50th−74th percentile, VG3: 75th−89th percentile, and VG4: 90th and above. Between 2006 and 2013, 27,272 patients underwent surgery for localized bladder cancer. The median OS was 59.66 months (95% CI: 57.79−61.77). OS improved significantly as caseload increased. The unadjusted median OS difference between VG1 and VG4 was 15.35 months (64.3 vs. 48.95 months, HR 1.19 95% CI: 1.13−1.25, p < 0.001) for FAC. This figure was 19.84 months (66.89 vs. 47.05 months, HR 1.25 95% CI: 1.18−1.32, p < 0.0001) for FASC. This analysis revealed a significant and clinically important survival advantage for curative bladder cancer surgery at highly experienced centers.

A simple daily dynamic feeding regimen for reducing phosphorus consumption and excretion in laying hens.

Phosphorus metabolism in laying hens is a highly dynamic process over the course of the 24 h egg-laying cycle. Adjusting the phosphorus feeding regimen according to the daily egg-laying cycle may help to improve phosphorus utilization efficiency. Hy-Line Brown layers (n = 120; 70 wk old) were offered 4 different phosphorus daily regimens: (1) RR, fed regular phosphorus at both 09:00 and 17:00; (2) RL, fed regular phosphorus at 09:00 and low phosphorus at 17:00; (3) LR, fed low phosphorus at 09:00 and regular phosphorus at 17:00; (4) LL, fed low phosphorus at both 09:00 and 17:00. The regular and low phosphorus diets contained 0.32% and 0.14% non-phytate phosphorus, respectively. The feeding trial lasted for 12 wk. As a result, layers on the RL regimen had decreased laying rate (P < 0.05; 5 to 8, 9 to 12, and 1 to 12 wk) when compared to all other regimens. Layers on the LL regimen had decreased eggshell thickness and specific gravity (P < 0.05; wk 8) when compared to all other regimens, and had decreased egg shell strength (P < 0.05; wk 8) when compared to RL and LR regimens. When compared to the RR regimen (a common practice in the industry), layers on the LR regimen had: (1) identical laying performance and egg quality (P > 0.05); (2) decreased phosphorus excretion (P < 0.05) during the period of 09:00 to 17:00; (3) increased jejunal calbindin D28k protein expression (P < 0.05) 2 h after feeding in the morning; (4) decreased serum fibroblast growth factor 23 and calcitriol levels (P < 0.05), decreased jejunal type III sodium-phosphate cotransporter 2 gene and protein expression (P < 0.05), and decreased renal type III sodium-phosphate cotransporter 1 protein expression (P < 0.05), 2 h after feeding in the afternoon. In summary, when dietary phosphorus was supplemented in accordance with daily serum phosphorus rhythms (i.e., the LR regimen), laying performance and egg quality were well supported whilst significantly decreasing phosphorus consumption and excretion. Thus, serum phosphorus rhythms will need to be carefully maintained when developing dietary phosphorus-reduction strategies in laying hens.

Miniature optoelectronic compound eye camera.

Inspired by insect compound eyes (CEs) that feature unique optical schemes for imaging, there has recently been growing interest in developing optoelectronic CE cameras with comparable size and functions. However, considering the mismatch between the complex 3D configuration of CEs and the planar nature of available imaging sensors, it is currently challenging to reach this end. Here, we report a paradigm in miniature optoelectronic integrated CE camera by manufacturing polymer CEs with 19~160 logarithmic profile ommatidia via femtosecond laser two-photon polymerization. In contrast to µ-CEs with spherical ommatidia that suffer from defocusing problems, the as-obtained µ-CEs with logarithmic ommatidia permit direct integration with a commercial CMOS detector, because the depth-of-field and focus range of all the logarithmic ommatidia are significantly increased. The optoelectronic integrated µ-CE camera enables large field-of-view imaging (90°), spatial position identification and sensitive trajectory monitoring of moving targets. Moreover, the miniature µ-CE camera can be integrated with a microfluidic chip and serves as an on-chip camera for real-time microorganisms monitoring. The insect-scale optoelectronic µ-CE camera provides a practical route for integrating well-developed planar imaging sensors with complex micro-optics elements, holding great promise for cutting-edge applications in endoscopy and robot vision.

Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. EXPERIMENTAL DESIGN: SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. RESULTS: PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. CONCLUSIONS: In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

Dietary vitamin D3 deprivation suppresses fibroblast growth factor 23 signals by reducing serum phosphorus levels in laying hens.

The present study was carried out to evaluate the effect of dietary supplemental vitamin D3 on fibroblast growth factor 23 (FGF23) signals as well as phosphorus homeostasis and metabolism in laying hens. Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments: 1) vitamin D3 restriction group (n = 7) fed 0 IU/kg vitamin D3 diet, and 2) regular vitamin D3 group (n = 7) fed 1,600 IU/kg vitamin D3 diet. The study lasted for 21 d. Serum parameters, phosphorus and calcium excretion status, and tissue expressions of type II sodium-phosphate co-transporters (NPt2), FGF23 signals and vitamin D3 metabolic regulators were determined. Hens fed the vitamin D3 restricted diet had decreased serum phosphorus levels (by 31.3%, P = 0.028) when compared to those fed regular vitamin D3 diet. In response to the decreased serum phosphorus, the vitamin D3 restricted laying hens exhibited: 1) suppressed kidney expressions of 25-hydroxyvitamin D 1-α-hydroxylase (CYP27B1, by 52.8%, P = 0.036) and 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1, by 99.4%, P = 0.032); 2) suppressed serum levels of FGF23 (by 14.6%, P = 0.048) and increased serum alkaline phosphatase level (by 414.1%, P = 0.012); 3) decreased calvaria mRNA expressions of fibroblast growth factor receptors (FGFR1, by 85.2%, P = 0.003, FGFR2, by 89.4%, P = 0.014, FGFR3, by 88.8%, P = 0.017, FGFR4, by 89.6%, P = 0.030); 4) decreased kidney mRNA expressions of FGFR1 (by 65.5%, P = 0.021), FGFR4 (by 66.0%, P = 0.050) and KLOTHO (by 68.8%, P = 0.038); 5) decreased kidney protein expression of type 2a sodium-phosphorus co-transporters (by 54.3%, P = 0.039); and 6) increased percent excreta calcium (by 26.9%, P = 0.002). In conclusion, the deprivation of dietary vitamin D3 decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

Insights on recent innovations in bladder cancer immunotherapy.

Bladder carcinoma is the most common genitourinary cancer, with a high prevalence and global incidence. In addition to early detection by cytology, the management of bladder cancer has recently advanced, not only by improvements in conventional treatments such as surgery and chemotherapy, but also through the introduction of immunotherapeutic strategies. The number of approved immunotherapeutic agents has dramatically increased, with various preclinical and clinical applications in cancer drug discovery. Some bladder cancer immunotherapies include immune checkpoint inhibitors, adoptive cell therapy, cytokine-based therapy, bispecific antibodies, and antibody-drug conjugates. This review provides an overview of some of the innovative immunotherapeutic agents approved and in development that can potentially be used in the treatment of bladder cancer.

PDXNet portal: patient-derived Xenograft model, data, workflow and tool discovery.

We created the PDX Network (PDXNet) portal (https://portal.pdxnetwork.org/) to centralize access to the National Cancer Institute-funded PDXNet consortium resources, to facilitate collaboration among researchers and to make these data easily available for research. The portal includes sections for resources, analysis results, metrics for PDXNet activities, data processing protocols and training materials for processing PDX data. Currently, the portal contains PDXNet model information and data resources from 334 new models across 33 cancer types. Tissue samples of these models were deposited in the NCI's Patient-Derived Model Repository (PDMR) for public access. These models have 2134 associated sequencing files from 873 samples across 308 patients, which are hosted on the Cancer Genomics Cloud powered by Seven Bridges and the NCI Cancer Data Service for long-term storage and access with dbGaP permissions. The portal includes results from freely available, robust, validated and standardized analysis workflows on PDXNet sequencing files and PDMR data (3857 samples from 629 patients across 85 disease types). The PDXNet portal is continuously updated with new data and is of significant utility to the cancer research community as it provides a centralized location for PDXNet resources, which support multi-agent treatment studies, determination of sensitivity and resistance mechanisms, and preclinical trials.

CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy.

Adoptive cell therapy with chimeric antigen receptor (CAR) immunotherapy has made tremendous progress with five CAR T therapies approved by the US Food and Drug Administration for hematological malignancies. However, CAR immunotherapy in solid tumors lags significantly behind. Some of the major hurdles for CAR immunotherapy in solid tumors include CAR T cell manufacturing, lack of tumor-specific antigens, inefficient CAR T cell trafficking and infiltration into tumor sites, immunosuppressive tumor microenvironment (TME), therapy-associated toxicity, and antigen escape. CAR Natural Killer (NK) cells have several advantages over CAR T cells as the NK cells can be manufactured from pre-existing cell lines or allogeneic NK cells with unmatched major histocompatibility complex (MHC); can kill cancer cells through both CAR-dependent and CAR-independent pathways; and have less toxicity, especially cytokine-release syndrome and neurotoxicity. At least one clinical trial showed the efficacy and tolerability of CAR NK cell therapy. Macrophages can efficiently infiltrate into tumors, are major immune regulators and abundantly present in TME. The immunosuppressive M2 macrophages are at least as efficient as the proinflammatory M1 macrophages in phagocytosis of target cells; and M2 macrophages can be induced to differentiate to the M1 phenotype. Consequently, there is significant interest in developing CAR macrophages for cancer immunotherapy to overcome some major hurdles associated with CAR T/NK therapy, especially in solid tumors. Nevertheless, both CAR NK and CAR macrophages have their own limitations. This comprehensive review article will discuss the current status and the major hurdles associated with CAR T and CAR NK therapy, followed by the structure and cutting-edge research of developing CAR macrophages as cancer-specific phagocytes, antigen presenters, immunostimulators, and TME modifiers.

Longitudinal Evaluation of Circulating Tumor DNA Using Sensitive Amplicon-Based Next-Generation Sequencing to Identify Resistance Mechanisms to Immune Checkpoint Inhibitors for Advanced Urothelial Carcinoma.

Serial evaluation of circulating tumor DNA may allow noninvasive assessment of drivers of resistance to immune checkpoint inhibitors (ICIs) in advanced urothelial cancer (aUC). We used a novel, amplicon-based next-generation sequencing assay to identify genomic alterations (GAs) pre- and post-therapy in 39 patients with aUC receiving ICI and 6 receiving platinum-based chemotherapy (PBC). One or more GA was seen in 95% and 100% of pre- and post-ICI samples, respectively, commonly in TP53 (54% and 54%), TERT (49% and 59%), and BRCA1/BRCA2 (33% and 33%). Clearance of ≥1 GA was seen in 7 of 9 patients responding to ICI, commonly in TP53 (n = 4), PIK3CA (n = 2), and BRCA1/BRCA2 (n = 2). A new GA was seen in 17 of 20 patients progressing on ICI, frequently in BRCA1/BRCA2 (n = 6), PIK3CA (n = 3), and TP53 (n = 3), which seldom emerged in patients receiving PBC. These findings highlight the potential for longitudinal circulating tumor DNA evaluation in tracking response and resistance to therapy.