Prostate fibroblasts and prostate cancer associated fibroblasts exhibit different metabolic, matrix degradation and PD-L1 expression responses to hypoxia.

Fibroblasts are versatile cells that play a major role in wound healing by synthesizing and remodeling the extracellular matrix (ECM). In cancers, fibroblasts play an expanded role in tumor progression and dissemination, immunosuppression, and metabolic support of cancer cells. In prostate cancer (PCa), fibroblasts have been shown to induce growth and increase metastatic potential. To further understand differences in the functions of human PCa associated fibroblasts (PCAFs) compared to normal prostate fibroblasts (PFs), we investigated the metabolic profile and ECM degradation characteristics of PFs and PCAFs using a magnetic resonance imaging and spectroscopy compatible intact cell perfusion assay. To further understand how PFs and PCAFs respond to hypoxic tumor microenvironments that are often observed in PCa, we characterized the effects of hypoxia on PF and PCAF metabolism, invasion and PD-L1 expression. We found that under normoxia, PCAFs displayed decreased ECM degradation compared to PFs. Under hypoxia, ECM degradation by PFs increased, whereas PCAFs exhibited decreased ECM degradation. Under both normoxia and hypoxia, PCAFs and PFs showed significantly different metabolic profiles. PD-L1 expression was intrinsically higher in PCAFs compared to PFs. Under hypoxia, PD-L1 expression increased in PCAFs but not in PFs. Our data suggest that PCAFs may not directly induce ECM degradation to assist in tumor dissemination, but may instead create an immune suppressive tumor microenvironment that further increases under hypoxic conditions. Our data identify the intrinsic metabolic, ECM degradation and PD-L1 expression differences between PCAFs and PFs under normoxia and hypoxia that may provide novel targets in PCa treatment.

Metabolic fingerprinting by nuclear magnetic resonance of hepatocellular carcinoma cells during p53 reactivation-induced senescence.

Cellular senescence is characterized by stable cell cycle arrest. Senescent cells exhibit a senescence-associated secretory phenotype that can promote tumor progression. The aim of our study was to identify specific nuclear magnetic resonance (NMR) spectroscopy-based markers of cancer cell senescence. For metabolic studies, we employed murine liver carcinoma Harvey Rat Sarcoma Virus (H-Ras) cells, in which reactivation of p53 expression induces senescence. Senescent and nonsenescent cell extracts were subjected to high-resolution proton (1H)-NMR spectroscopy-based metabolomics, and dynamic metabolic changes during senescence were analyzed using a magnetic resonance spectroscopy (MRS)-compatible cell perfusion system. Additionally, the ability of intact senescent cells to degrade the extracellular matrix (ECM) was quantified in the cell perfusion system. Analysis of senescent H-Ras cell extracts revealed elevated sn-glycero-3-phosphocholine, myoinositol, taurine, and creatine levels, with decreases in glycine, o-phosphocholine, threonine, and valine. These metabolic findings were accompanied by a greater degradation index of the ECM in senescent H-Ras cells than in control H-Ras cells. MRS studies with the cell perfusion system revealed elevated creatine levels in senescent cells on Day 4, confirming the 1H-NMR results. These senescence-associated changes in metabolism and ECM degradation strongly impact growth and redox metabolism and reveal potential MRS signals for detecting senescent cancer cells in vivo.

OsteoMac: A new player on the bone biology scene.

The knowledge of bone biology has undergone major advances in recent decades. In bone, resorbing osteoclasts have classically been described as tissue-resident macrophages, however, it is currently known that a new subtype of macrophages, called OsteoMacs, are specialised bone-resident macrophages, which, depending on certain conditions, may play an important role not only in bone homeostasis, but also in promoting pro-anabolic functions or in creating an inflammatory environment. There is growing evidence that these osteal macrophages may influence the development of bone-loss diseases. It is essential to understand the biological bases underlying bone physiological processes to search for new therapeutic targets for bone-loss diseases, such as osteoporosis, rheumatoid arthritis, or even periodontal disease. This narrative review provides an update on the origin, characterisation, and possible roles of osteoMacs in bone biology. Finally, the potential clinical applications of this new cell in bone-loss disorders are discussed.

Antibiotics against Pseudomonas aeruginosa on Human Skin Cell Lines: Determination of the Highest Non-Cytotoxic Concentrations with Antibiofilm Capacity for Wound Healing Strategies.

Pseudomonas aeruginosa is one of the most common microorganisms causing infections of severe skin wounds. Antibiotic or antiseptic treatments are crucial to prevent and curb these infections. Antiseptics have been reported to be cytotoxic to skin cells and few studies evaluate the impact of commonly used antibiotics. This study evaluates how clinical antibiotics affect skin cells' viability, proliferation, migration, and cytokine secretion and defines the highest non-cytotoxic concentrations that maintain antibacterial activity. Cell proliferation, viability, and migration were evaluated on cell monolayers. Cytokines related to the wound healing process were determined. The minimum inhibitory concentrations and the impact on bacterial biofilm were assessed. Results showed that 0.02 mg/mL ciprofloxacin and 1 mg/mL meropenem are the highest non-cytotoxic concentrations for fibroblasts and keratinocytes while 1.25 mg/mL amikacin and 0.034 mg/mL colistin do not affect fibroblasts' viability and cytokine secretion but have an impact on keratinocytes. These concentrations are above the minimum inhibitory concentration but only amikacin could eradicate the biofilm. For the other antibiotics, cytotoxic concentrations are needed to eradicate the biofilm. Combinations with colistin at non-cytotoxic concentrations effectively eliminate the biofilm. These results provide information about the concentrations required when administering topical antibiotic treatments on skin lesions, and how these antibiotics affect wound management therapies. This study set the basis for the development of novel antibacterial wound healing strategies such as antibiotic artificial skin substitutes.

mRNA Levels of Aromatase, 5α-Reductase Isozymes, and Prostate Cancer-Related Genes in Plucked Hair from Young Men with Androgenic Alopecia.

Androgenic alopecia (AGA) is the most prevalent type of progressive hair loss and has psychological repercussions. Nevertheless, the effectiveness of current pharmacological treatments remains limited, in part because the molecular basis of the disease has not been fully elucidated. Our group previously highlighted the important roles of aromatase and 5α-reductase (5α-R) in alopecia in young women with female pattern hair loss. Additionally, an association has been proposed between AGA and prostate cancer (PCa), suggesting that genes implicated in PCa would also be involved in AGA. A low-invasive, sensitive, and precise method was used to determine mRNA levels of aromatase, 5α-R isozymes, and 84 PCa-related genes in samples of plucked hair from young men with AGA and controls. Samples were obtained with a trichogram from the vertex scalp, and mRNA levels were quantified using real-time RT-PCR. The men with AGA had significantly higher 5α-R2 mRNA levels in comparison to controls; interestingly, some of them also showed markedly elevated mRNA levels of 5α-R1 or 5α-R3 or of both, which may explain the varied response to 5α-R inhibitor treatments. The men with AGA also showed significant changes versus controls in 6 out of the 84 genes implicated in PCa. This study contributes greater knowledge of the molecular bases of AGA, facilitating early selection of the most appropriate pharmacological therapy and opening the way to novel treatments.

Fast and Reliable Sending of Generic Object Oriented Substation Event Frames between Remote Locations over Loss-Prone Networks.

WAMPAC (Wide Area Monitoring Protection and Control) applications are becoming crucial for granting a stable operation of the electricity transmission grid. These systems use a set of sensors distributed between different electrical substations to gather real-time measurements from the field. These sensors are called Phasor Measurement Units (PMUs). Using the gathered data, different monitoring, protection, and control algorithms are run in a Phasor Data Concentrator (PDC) located in a central location. These algorithms close the loop via the generation of remedial commands, which are sent back to the field level with stringent delay, security, and reliability requirements. GOOSE (Generic Object Oriented Substation Events) protocol, defined by IEC 61850 (IEC stands for International Electrotechnical Commission), is used for that aim and also considers the option of sending these commands over IP networks (this option is called Routed-GOOSE). The present article proposes two alternatives for the tunneling of GOOSE frames over IP. Both options allow the decoupling of the transmission and the security aspects, thus increasing flexibility and allowing for easier deployment. The first option, called VX-GOOSE, is a combination of standard protocols, allowing the sending of these frames over UDP/IP tunnels. The tests that have been carried out demonstrate that, under certain network conditions, the transmission of GOOSE frames over UDP may fail, and in some extreme cases, even a whole burst of GOOSEs could be lost. This may have very bad consequences for a distributed electrical system. It should be noted that this limitation affects both VX-GOOSE and Routed-GOOSE. To overcome these limitations, the second option, called Simplemux blast mode, includes a novel mechanism that provides delivery guarantees and a reduced delay, with the counterpart of a certain degree of redundancy. As shown in the experiments, the incurred delays can be significantly reduced when remote locations are connected via unreliable networks, whereas the bandwidth increase caused by redundancy can be kept at reasonable levels. Finally, it should be remarked that although GOOSE is a relevant example use case, this approach can be applied in other fields where flows require very low delay and delivery guarantees.

Effect of the use of platelet concentrates on new bone formation in alveolar ridge preservation: a systematic review, meta-analysis, and trial sequential analysis.

OBJECTIVES: To investigate the histomorphometric changes occurring in alveolar ridge preservation (ARP) based on the use of different plasma concentrates (PCs) in randomized clinical trials (RCT). There is controversy whether the placement of PCs in ARP is effective in the formation of new bone. MATERIALS AND METHODS: A systematic review search was conducted in PubMed, Scopus, Web of Science, and Cochrane Database to answer the PICO question: In patients undergoing tooth extraction followed by ARP, do PCs alone in the post-extraction socket in comparison with spontaneous healing improve new vital bone formation percentage in histomorphometric analysis after more than 10 weeks? The risk of bias was assessed and a meta-analysis was conducted. RESULTS: Of 3809 results, 8 studies were considered suitable for inclusion. A total of 255 teeth were extracted in 250 patients. Regarding the PCs used, ARP was performed with platelet- and leukocyte-rich fibrin (L-PRF) in 120 sockets, and with pure platelet-rich plasma (P-PRP) in 31 sockets and 104 sockets were controlled. PCs improved new bone formation in ARP with respect to the spontaneous healing group (SMD = 1.77, 95%C.I. = 1.47-2.06, p-value < 000.1). There were no differences between the different PCs (L-PRF and P-PRP). CONCLUSION: The results of this meta-analysis support the efficacy of the use of PCs in new bone formation in ARP. With respect to the different types of PCs studied, no differences were observed. CLINICAL RELEVANCE: When planning implant surgery after tooth extraction, treatment with PCs should be considered for ARP. Any PC increases new bone formation compared to spontaneous healing.

Discordant results for ALK based on immunohistochemistry versus fluorescence in situ hybridization in a cohort of patients diagnosed with lung adenocarcinoma / Discordancia de los resultados para ALK basados en inmunohistoquímica e hibridación fluorescente in situ en una cohorte de pacientes diagnosticados con adenocarcinoma de pulmón

Introduction: Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. Methods: To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. Results: Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. Conclusions: Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.(AU)

Introducción: La reorganización de la (anaplastic lymphoma kinase) ALK ubicada en el brazo corto del cromosoma 2, región 2 y banda 3 es frecuente en los pacientes con cáncer de pulmón que responden a terapias dirigidas con inhibidores de la ALK. Por ello, su identificación se ha establecido como una prueba diagnóstica estándar en pacientes con CPCNP, ya que dichas alteraciones cromosómicas puedan determinar la activación de importantes vías de señalización implicadas en la supervivencia y proliferación celulares. Métodos: Para determinar el estatus de gen ALK se realizaron pruebas FISH e IHC en 18 pacientes con adenocarcinoma pulmonar, 12 mujeres y 6 varones, con edades comprendidas entre 29 y 85 años. Las muestras fueron analizadas en el Departamento de Anatomía Patológica del Hospital Universitario San Ignacio. Resultados: Los resultados entre ambas técnicas mostraron patrones discordantes en 5 pacientes, con positividad de FISH y negatividad con IHC. El límite para definir la positividad de ALK se estableció en el 15%. Estos resultados muestran evidencia experimental que dichas técnicas difieren en situaciones específicas. Conclusiones: Este estudio recomienda la investigación del estatus del gen ALK en los pacientes con sospecha de cáncer de pulmón, mediante la combinación de FISH e IHC.(AU)

Discordant results for ALK based on immunohistochemistry versus fluorescence in situ hybridization in a cohort of patients diagnosed with lung adenocarcinoma.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. METHODS: To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. RESULTS: Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. CONCLUSIONS: Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.

Skin wound healing improvement in diabetic mice through FTIR microspectroscopy after implanting pluripotent stem cells.

Diabetes is a chronic degenerative disease that carries multiple complications. One of the most important complications is the diabetic cutaneous complications, such as skin lesions, ulcerations, and diabetic foot, which are present in 30%-70% of the patients. Currently, the treatments for wound healing include growth factors and cytokines, skin substitutes, hyperbaric oxygen therapy, and skin grafts. However, these treatments are ineffective due to the complex mechanisms involved in developing unhealed wounds. Considering the aforementioned complications, regenerative medicine has focused on this pathology using stem cells to improve these complications. However, it is essential to mention that there is a poor biomolecular understanding of diabetic skin and the effects of treating it with stem cells. For this reason, herein, we investigated the employment of pluripotent stem cells (PSC) in the wound healing process by carrying out morphometric, histological, and Fourier-transform infrared microspectroscopy (FTIRM) analysis. The morphometric analysis was done through a photographic follow-up, measuring the lesion areas. For the histological analysis, hematoxylin & eosin and picrosirius red stains were used to examine the thickness of the epidermis and the cellularity index in the dermis as well as the content and arrangement of collagen type I and III fibers. Finally, for the FTIRM analysis, skin cryosections were obtained and analyzed by employing a Cassegrain objective of 16× of an FTIR microscope coupled to an FTIR spectrometer. For this purpose, 20 mice were divided into two groups according to the treatment they received: the Isotonic Salt Solution (ISS) group and the PSCs group (n = 10). Both groups were induced to diabetes, and six days after diabetes induction, an excisional lesion was made in the dorsal area. Furthermore, using microscopy and FTIRM analysis, the skin healing process on days 7 and 15 post-skin lesion excision was examined. The results showed that the wound healing process over time, considering the lesion size, was similar in both groups; however, the PSCs group evidenced hair follicles in the wound. Moreover, the histological analysis evidenced that the PSCs group exhibited granulation tissue, new vessels, and better polarity of the keratinocytes. In addition, the amount of collagen increased with a good deposition and orientation, highlighting that type III collagen fibers were more abundant in the PSCs. Finally, the FTIR analysis evidenced that the PSCs group exhibited a faster wound healing process. In conclusion, the wounds treated with PSCs showed a more rapid wound healing process, less inflammatory cellular infiltration, and more ordered structures than the ISS group.

Efficacy and safety of a bioadhesive gel containing propolis extract, nanovitamin C and nanovitamin E on desquamative gingivitis: a double-blind, randomized, clinical trial.

OBJECTIVES: To evaluate the efficacy of a gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to professional plaque removal on desquamative gingivitis (DG). MATERIALS AND METHODS: A randomized clinical trial was conducted on patients suffering DG due to mucocutaneous diseases. Patients received professional supragingival prophylaxis with oral hygiene instructions and were randomly assigned to use test or control gels as toothpaste and to apply it on DG lesions 3 times/day for 4 weeks. DG clinical score (DGCS), clinical periodontal variables, and visual analog scale (VAS) for pain and oral health impact profile (OHIP-14) were collected at baseline, 2 and 4 weeks. RESULTS: Twenty-two patients were randomly assigned to test (n = 11) or control group (n = 11). Eighteen had diagnosis of oral lichen planus and four of mucous membrane pemphigoid. DGCS statistically decreased in both groups after treatment with no significant differences between groups. Clinical periodontal outcomes decreased in both groups, but no significant differences were observed. Periodontal variables statistically improved only in test group after treatment. VAS and OHIP-14 scores decreased in test and control groups without significant differences. However, only one test group showed a statistically significant decrease in VAS and OHIP-14 scores after treatment. No adverse effects were reported. CONCLUSIONS: Test gel may alleviate DG and improve quality of life without side effects. CLINICAL RELEVANCE: A gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to mechanical debridement may improve both clinical and patient related outcomes in DG patients without side effects. CLINICAL TRIAL REGISTRATION: The study protocol was registered at clinicaltrials.gov with the following number: NCT05124366 on October 16, 2021.

Correction: Torres et al. Twentieth-Century Paleoproteomics: Lessons from Venta Micena Fossils. Biology 2022, 11, 1184.

There was an error in the original publication [...].

Plasma rich in growth factors (PRGF) and leukocyte-platelet rich fibrin (L-PRF): comparative release of growth factors and biological effect on osteoblasts.

PURPOSE: To compare the release of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-I) and interleukin 1ß (IL-1ß) of plasma rich in growth factors (PRGF) and leucocyte platelet-rich fibrin (L-PRF) and to evaluate their biological implication in osteoblasts. METHODS: Blood from 3 healthy volunteers was processed into PRGF, immediate L-PRF (L-PRF 0') and L-PRF 30 min after collection (L-PRF-30') and a control group. Growth factors release were analyzed at 7 times by ELISA. Cell proliferation, collagen-I synthesis and alkaline phosphatase activity were assessed in primary cultures of human osteoblasts. RESULTS: A slower controlled release of IGF-I, VEGF and PDGF was observed in the PRGF group at day 14. A higher synthesis of type I collagen was also quantified in PRGF. L-PRF released significantly higher amounts of IL-1ß, that was almost absent in the PRGF. CONCLUSIONS: The addition of leukocytes dramatically increases the secretion of proinflammatory cytokines, which are likely to negatively influence the synthesis of type I collagen and alkaline phosphatase (ALP) by osteoblasts.

Twentieth-Century Paleoproteomics: Lessons from Venta Micena Fossils.

Proteomics methods can identify amino acid sequences in fossil proteins, thus making it possible to determine the ascription or proximity of a fossil to other species. Before mass spectrometry was used to study fossil proteins, earlier studies used antibodies to recognize their sequences. Lowenstein and colleagues, at the University of San Francisco, pioneered the identification of fossil proteins with immunological methods. His group, together with Olivares's group at the University of Granada, studied the immunological reactions of proteins from the controversial Orce skull fragment (VM-0), a 1.3-million-year-old fossil found at the Venta Micena site in Orce (Granada province, southern Spain) and initially assigned to a hominin. However, discrepancies regarding the morphological features of the internal face of the fossil raised doubts about this ascription. In this article, we review the immunological analysis of the proteins extracted from VM-0 and other Venta Micena fossils assigned to hominins and to other mammals, and explain how these methods helped to determine the species specificity of these fossils and resolve paleontological controversies.

Two diverse carriers are better than one: A case study in α-particle therapy for prostate specific membrane antigen-expressing prostate cancers.

Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α-particles that exhibit only a 4-5 cell-diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α-particles are likely not to be killed. This study aims to mechanistically understand a delivery strategy to uniformly distribute α-particles within established solid tumors by simultaneously delivering the same α-particle emitter by two diverse carriers, each killing a different region of the tumor: (1) the cancer-agnostic, but also tumor-responsive, liposomes engineered to best irradiate tumor regions far from the vasculature, and (2) a separately administered, antibody, targeting any cancer-cell's surface marker, to best irradiate the tumor perivascular regions. We demonstrate that on a prostate specific membrane antigen (PSMA)-expressing prostate cancer xenograft mouse model, for the same total injected radioactivity of the α-particle emitter Actinium-225, any radioactivity split ratio between the two carriers resulted in better tumor growth inhibition compared to the tumor inhibition when the total radioactivity was delivered by any of the two carriers alone. This finding was due to more uniform tumor irradiation for the same total injected radioactivity. The killing efficacy was improved even though the tumor-absorbed dose delivered by the combined carriers was lower than the tumor-absorbed dose delivered by the antibody alone. Studies on spheroids with different receptor-expression, used as surrogates of the tumors' avascular regions, demonstrated that our delivery strategy is valid even for as low as 1+ (ImmunoHistoChemistry score) PSMA-levels. The findings presented herein may hold clinical promise for those established tumors not being effectively eradicated by current α-particle radiotherapies.

Facemasks: Perceptions and use in an ED population during COVID-19.

STUDY OBJECTIVE: Facemask use is associated with reduced transmission of SARS-CoV-2. Most surveys assessing perceptions and practices of mask use miss the most vulnerable racial, ethnic, and socio-economic populations. These same populations have suffered disproportionate impacts from the pandemic. The purpose of this study was to assess beliefs, access, and practices of mask wearing across 15 urban emergency department (ED) populations. METHODS: This was a secondary analysis of a cross-sectional study of ED patients from December 2020 to March 2021 at 15 geographically diverse, safety net EDs across the US. The primary outcome was frequency of mask use outside the home and around others. Other outcome measures included having enough masks and difficulty obtaining them. RESULTS: Of 2,575 patients approached, 2,301 (89%) agreed to participate; nine had missing data pertaining to the primary outcome, leaving 2,292 included in the final analysis. A total of 79% of respondents reported wearing masks "all of the time" and 96% reported wearing masks over half the time. Subjects with PCPs were more likely to report wearing masks over half the time compared to those without PCPs (97% vs 92%). Individuals experiencing homelessness were less likely to wear a mask over half the time compared to those who were housed (81% vs 96%). CONCLUSIONS: Study participants reported high rates of facemask use. Respondents who did not have PCPs and those who were homeless were less likely to report wearing a mask over half the time and more likely to report barriers in obtaining masks. The ED may serve a critical role in education regarding, and provision of, masks for vulnerable populations.

Impact of chronic exposure of rats to bisphenol A from perinatal period to adulthood on intraprostatic levels of 5α-reductase isozymes, aromatase, and genes implicated in prostate cancer development.

The synergetic effect of estrogens and androgens is known to play a crucial role in the physiopathology of the prostate gland. Bisphenol A (BPA) is an endocrine disrupting compound that can interfere with endocrine hormone functioning and thereby influence prostate development. The objective of this study was to examine the impact on prostate expression of aromatase, 5α-R isozymes, and prostate cancer-related genes of exposure to low doses of BPA from perinatal period to adulthood. Vehicle or BPA (2.5 µg/kg b.w./day) was administered to gestating Wistar rats from gestational day 12 (GD12) to parturition and then to their male pups from postnatal day 1 (PND1) until euthanization on PND90. Their prostate glands were examined by qRT-PCR, Western blot, PCR array, and morphological study. mRNA and protein levels of 5α-R2 were significantly reduced and mRNA and protein levels of aromatase were significantly increased in BPA-treated animals, which also showed modifications of 8 out of the 84 key genes implicated in the development of prostate cancer. Because BPA interferes with genes involved in intraprostatic androgen and estrogen production and others implicated in prostate cancer, research is warranted into the prostate disease risk associated with chronic low-dose BPA exposure throughout life.

Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered α-Particles May Realize the Promise for 225Ac in Large, Solid Tumors.

α-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e., large, vascularized) soft-tissue lesions, the diffusion-limited penetration depths of radiolabeled antibodies or nanocarriers (≤50-80 µm) combined with the short range of α-particles (4-5 cell diameters) may result in only partial tumor irradiation, potentially limiting treatment efficacy. To address this challenge, we combined carriers with complementary intratumoral microdistributions of the delivered α-particles. We used the α-particle generator 225Ac, and we combined a tumor-responsive liposome (which, on tumor uptake, releases into the interstitium a highly diffusing form of its radioactive payload [225Ac-DOTA], potentially penetrating the deeper parts of tumors where antibodies do not reach) with a separately administered, less-penetrating radiolabeled antibody (irradiating the tumor perivascular regions where liposome contents clear too quickly). Methods: In a murine model with orthotopic human epidermal growth factor receptor 2-positive BT474 breast cancer xenografts, the biodistributions of each carrier were evaluated, and the control of tumor growth was monitored after administration of the same total radioactivity of 225Ac delivered by the 225Ac-DOTA-encapsulating liposomes, by the 225Ac-DOTA-SCN--labeled trastuzumab, and by both carriers at equally split radioactivities. Results: Tumor growth was significantly more inhibited when the same total injected radioactivity was divided between the 2 separate carriers than when delivered by either of the carriers alone. The combined carriers enabled more uniform intratumoral microdistributions of α-particles, at a tumor dose that was lower than the dose delivered by the antibody alone. Conclusion: This strategy demonstrates that more uniform microdistributions of the delivered α-particles within established solid tumors improve efficacy even at lower tumor doses. Augmentation of antibody-targeted α-particle therapies with tumor-responsive liposomes may address partial tumor irradiation, improving therapeutic effects.

Salivary LDH in oral cancer and potentially malignant disorders: A systematic review and meta-analysis.

OBJECTIVES: To evaluate whether salivary lactate dehydrogenase (LDH) levels are increased in patients with oral cancer (OC) or oral potentially malignant disorders (OPMD) when compared to a healthy control group (CG). MATERIAL AND METHODS: We conducted a comprehensive search of specialized databases (PubMed/MEDLINE, The Cochrane Library, Web of Science, Scopus, and OpenGrey), including observational analytical studies evaluating the salivary LDH levels (in UI/L or µ/L) in OC or OPMD patients and compared them with a CG. RESULTS: Thirteen case-control studies were included. A total of 755 patients were evaluated, including 303 OC cases, 149 OPMD cases, and 303 controls. The meta-analysis showed that LDH levels were higher within the OC group than the CG (SMD 9.49; 95% CI 6.97-12; p = .00001). Patients with oral leucoplakia (SMD 11.67; 95% CI 1.01-22.33; p = .03) and oral submucous fibrosis (SMD 25.83; 95% CI -1.74-53.40; p = .07) also presented higher levels than the CG. In addition, OC patients had higher salivary LDH levels than oral leucoplakia patients (SMD 5.62; 95% CI 2.14-9.11; p = .002). Heterogeneity was high across all the evaluated studies. CONCLUSIONS: The determination of salivary LDH may be a useful method for screening and tracking OC and OPMD, but new protocolized studies are required to establish precise cutoff values.