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Investigating the relationship between the physical environment and organismal adaptation is crucial to understanding the selective pressures that drive mammalian evolution. Of the varied approaches to exploring this relationship, macroscopic tooth wear analyses have become widely used due to their economic and simple methodologies. However, more work is needed to understand how assessments of wear patterns operate within finer levels of dietary and environmental contexts. It is specifically unclear if and how tooth wear differs inter‐ and intraspecifically between geographically widespread, large‐bodied mammalian populations. This project characterizes molar hypsodonty indices and mesowear scores of white‐tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus) populations across North and Central America, investigating if and how molar wear and morphology vary over the deer's large and ecologically variable geographic distribution. While mesowear scores generally do not strongly track environmental signals within and between Odocoileus species, hypsodonty indices reveal a strong correlation between crown height and aridity, which likely represents an adaptive response to abrasive diets in areas with low precipitation. [ABSTRACT FROM AUTHOR]

Background and purposeDSC perfusion has been increasingly used in conjunction with other contrast-enhanced MR applications and therefore there is need for contrast-dose reduction when feasible. The purpose of this study was to establish the feasibility of reduced-contrast-dose brain DSC perfusion by using a probabilistic Bayesian method and to compare the results with the commonly used singular value decomposition technique.Materials and methodsHalf-dose (0.05-mmol/kg) and full-dose (0.1-mmol/kg) DSC perfusion studies were prospectively performed in 20 patients (12 men; 34-70 years of age) by using a 3T MR imaging scanner and a gradient-EPI sequence (TR/TE, 1450/22 ms; flip angle, 90°). All DSC scans were processed with block circulant singular value decomposition and Bayesian probabilistic methods. SNR analysis was performed in both half-dose and full-dose groups. The CBF, CBV, and MTT maps from both full-dose and half-dose scans were evaluated qualitatively and quantitatively in both WM and GM on coregistered perfusion maps. Statistical analysis was performed by using a t test, regression, and Bland-Altman analysis.ResultsThe SNR was significantly (P < .0001) lower in the half-dose group with 32% and 40% reduction in GM and WM, respectively. In the half-dose group, the image-quality scores were significantly higher in Bayesian-derived CBV (P = .02) and MTT (P = .004) maps in comparison with block circulant singular value decomposition. Quantitative values of CBF, CBV, and MTT in Bayesian-processed data were comparable and without a statistically significant difference between the half-dose and full-dose groups. The block circulant singular value decomposition-derived half-dose perfusion values were significantly different from those of the full-dose group both in GM (CBF, P < .001; CBV, P = .02; MTT, P = .02) and WM (CBF, P < .001; CBV, P = .003; MTT, P = .01).ConclusionsReduced-contrast-dose (0.05-mmol/kg) DSC perfusion of the brain is feasible at 3T by using the Bayesian probabilistic method with quantitative results comparable with those of the full-dose protocol.

Background: Performing an extended pelvic lymph node dissection (PLND) on all men with intermediate- and high-risk prostate cancer at the time of a radical prostatectomy (RP) remains controversial. The majority of patients PLND histology is benign, and the long-term cancer-free progression in men with positive lymph node metastasis is low. The objective is to investigate the probability of long-term biochemical freedom from recurrent disease (bNED) in men with lymph node metastasis identified at the time of radical prostatectomy (RP). Subjects and methods: A retrospective review of the pathology of 1184 pelvic lymph node dissections performed at the time of a radical prostatectomy by multiple surgeons referred to a single uro-pathology laboratory between 2008 and 2014 identified 61 men with node-positive prostate cancer. Of the men with positive nodes, 24 had a standard PLND and 37 an extended PLND (ePLND). bNED was defined as a post-operative serum PSA < 0.2 ng/ml. Results: The median follow-up is 4 years (2-8). The median lymph node count was 7 (range 2-16) for PLND and 22 (range 6-46) for the ePLND. A single lymph node metastasis was identified in 56% of the 61 men. Only 10% of men with a positive lymph node metastasis remained free of biochemical recurrence of disease, and only 5% had undetectable serum PSA. There was no difference in bNED outcome between a PLND and ePLND. The number of men needed to be treated with a PLND at the time of RP (NNT) to result in an undetectable post-operative PSA at a median follow-up of 4 years is 395. Conclusions: In men with lymph node metastasis, the probability of long-term bNED is low and the NNT for cure is high. With emerging improved radiological imaging techniques increasing the detection of lymph node metastasis outside the extended lymph node dissection templates, more scientific investigation is required to evaluate which men will benefit from a PLND and which men can avoid an unnecessary PLND procedure. [ABSTRACT FROM AUTHOR]

Pleural mesothelioma (PM) is a fatal disease with limited treatment options. Recently, PM management has improved with the development of immune checkpoint inhibitors (ICIs). In first-line therapy, dual PD-1 and CTLA-4 blockade enhances tumor control and patient survival compared with chemotherapy. Unfortunately, only a fraction of patients is responsive to immunotherapy, and approaches to reshape the tumor immune microenvironment and make ICIs more effective are urgently required. Here, we evaluated the effect of Hyperthermic IntraThOracic Chemotherapy (HITOC), a treatment that combines fever-range hyperthermia with local intrapleural cisplatin chemotherapy, on the tumor immune microenvironment and response to ICIs. To do this, we developed a murine PM model of HITOC. We found that HITOC significantly improved tumor control and animal survival through a mechanism involving the development of a cytotoxic immune response. Additionally, HITOC enhanced immune checkpoint expression by T lymphocytes and synergized with dual PD-1 and CTLA-4 inhibition, leading to further improvement in animal survival. Finally, the analysis of peritoneal mesothelioma patient samples treated by pressurized intraperitoneal aerosol chemotherapy (PIPAC) revealed a similar immunomodulation. In conclusion, HITOC remodels the tumor immune microenvironment of PM by promoting T-cell infiltration into the tumor and could be considered in combination with ICIs in the context of a clinical trial.

Brain metastases (BMs) are the most prevalent type of cerebral tumor, significantly affecting survival. In adults, lung cancer, breast cancer, and melanoma are the primary cancers associated with BMs. Symptoms often result from brain compression, and patients may present to the emergency department (ED) with life-threatening conditions. The goal of treatment of BMs is to maximize survival and quality of life by choosing the least toxic therapy. Surgical resection followed by cavity radiation or definitive stereotactic radiosurgery remains the standard approach, depending on the patient's condition. Conversely, whole brain radiation therapy is becoming more limited to cases with multiple inoperable BMs and is less frequently used for postoperative control. BMs often signal advanced systemic disease, and patients usually present to the ED with poorly controlled symptoms, justifying hospitalization. Over half of patients with BMs in the ED are admitted, making effective ED-based management a challenge. This article reviews the epidemiology, clinical manifestations, and current treatment options of patients with BMs. Additionally, it provides an overview of ED management and highlights the challenges faced in this setting. An improved understanding of the reasons for potentially avoidable hospitalizations in cancer patients with BMs is needed and could help emergency physicians distinguish patients who can be safely discharged from those who require observation or hospitalization.

Expansion of antigen-experienced CD8 + T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer 1 . Interleukin-2 (IL-2) acts as a key regulator of CD8 + cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability 2,3 . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE 2 ), a known negative regulator of immune response in the tumour microenvironment 4,5 , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 + TILs via the PGE 2 receptors EP2 and EP4. Mechanistically, PGE 2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ c chain, resulting in defective assembly of IL-2Rβ-IL2Rγ c membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE 2  signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE 2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential., (© 2024. The Author(s).)

Background Saliva has a powerful antioxidant activity proposing that it might have a protective role in the oral cavity. It is yet unclear, how circadian rhythm might affect this activity. Objective The main goal of this study was to compare the antioxidant status of saliva in patients with periodontal diseases (PD) to that of healthy people on a diurnal basis. Material and methods A total of 18 periodontal healthy individuals and 18 patients with chronic periodontitis were chosen. Samples of saliva were collected in the morning between 6:00 and 8:00 and in the evening between 6:00 and 8:00 (both stimulated and non-stimulated). The amount of glutathione (GSH), malondialdehyde (MDA), and total antioxidant status (TAS) in the salivary samples were analyzed, and its flow was also assessed. In addition, the scavenging capacity of saliva was tested in three systems generating oxygen free radicals. Results Results showed that GSH and TAS concentrations in the evening saliva of healthy subjects were significantly higher than those in the morning saliva, while MDA levels decreased (p<0.05). Conversely, there was no significant increase in GSH and TAS levels in the evening saliva of subjects with PD, and lipid peroxidation remained constant. On the other hand, the evening saliva of healthy subjects but not of subjects with PD was significantly more potent in scavenging free radicals in vitro than the morning saliva, especially for the superoxide (O2.-) radical (p<0.05). Moreover, scavenging activity was higher in stimulated than non-stimulated saliva. This activity was higher in evening saliva compared to the morning one and greater in healthy subjects compared to patients with PD (p<0.05). Conclusion A balance exists between oxidative stress and antioxidant mechanisms to maintain homeostasis in the oral cavity. This balance is deregulated in patients with PD as their saliva is unable to properly scavenge free radicals that might potentially increase over the day. Antioxidant supplements may be used in accordance with the circadian rhythm to minimize oxidative damage., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Diab et al.)

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Purpose: To develop and validate a micro-ultrasound risk score that predicts the likelihood of significant prostate cancer in the anterior zone., Methods: Patients were enrolled from three expert institutions familiar with micro-ultrasound. The study was conducted in two phases. First, the PRI-MUS anterior score was developed by assessing selected prostate videos from patients who subsequently underwent radical prostatectomy. Second, seven urology readers with varying levels of experience in micro-ultrasound examination evaluated prostate loops according to the PRI-MUS anterior score. Each reader watched the videos and recorded the likelihood of the presence of significant cancer in the anterior part of the prostate in a three-point scale. The coherence among the readers was calculated using the Fleiss kappa and the Cronbach alpha., Results: A total of 102 selected prostate scans were used to develop the risk assessment for anterior zone cancer in the prostate. The score comprised three categories: likely, equivocal, and unlikely. The median (IQR) sensitivity, specificity, positive predictive value, and negative predictive value for the seven readers were 72% (68-84), 68% (64-84), 75% (72-81), and 73% (71-80), respectively. The mean SD ROC AUC was 0.75 ± 2%, while the Fleiss kappa and the Cronbach alpha were 0.179 and 0.56, respectively., Conclusion: Micro-ultrasound can detect cancerous lesions in the anterior part of the prostate. When combined with the PRI-MUS protocol to assess the peripheral part, it enables an assessment of the entire prostate gland. Pending external validation, the PRI-MUS anterior score developed in this study might be implemented in clinical practice., (© 2023. The Author(s).)

Hemoptysis in cancer patients can occur for various reasons, including infections, tumors, blood vessel abnormalities and inflammatory conditions. The degree of hemoptysis is commonly classified according to the quantity of blood expelled. However, volume-based definitions may not accurately reflect the clinical impact of bleeding. This review explores a more comprehensive approach to evaluating hemoptysis by considering its risk factors, epidemiology and clinical consequences. In particular, this review provides insight into the risk factors, identifies mortality rates associated with hemoptysis in cancer patients and highlights the need for developing a mortality prediction score specific for cancer patients. The use of hemoptysis-related variables may help stratify patients into risk categories; optimize the control of bleeding with critical care; implement the use of tracheobronchial or vascular interventions; and aid in treatment planning. Effective management of hemoptysis in cancer patients must address the underlying cause while also providing supportive care to improve patients' quality of life.

Background: Drug hypersensitivity reactions (DHRs) are becoming more common as a result of increasing prevalence and case complexity. Allergists and clinical immunologists worldwide are challenged daily to adequately diagnose and manage these reactions. Data in the literature regarding DHR outpatient consultations are scarce worldwide, limited in the Middle East, and currently unavailable in Lebanon., Objective: This retrospective study aimed to evaluate the characteristics of all reported DHRs over 10 years in a tertiary-care allergy clinic in Lebanon., Methods: We conducted a decade-long (2012-21) retrospective analysis of the archived medical records of patients with a history of DHRs. Demographics, clinical history, diagnostic tools, and characteristics of the DHRs were collected and analyzed., Results: A total of 758 patients experienced DHRs to therapeutic molecules provided for ambulatory care. Our results identified 72 medications. The most frequently implicated drug classes included β-lactam antibiotics (53.8%), followed closely by nonsteroidal anti-inflammatory drugs (48.9%). Of the 758 patients, 32.6% reported DHRs to multiple molecules, and 11.8% reported concomitant DHRs to 1 or several molecules provided in the perioperative setting. Of those, opioids and neuromuscular blocking agents were the 2 most common therapeutic classes. Furthermore, we evaluated the cross-reactivity between molecules of the same class. In neuromuscular blocking agents, rocuronium and cisatracurium were the most commonly cross-reactive, and for opioids, the most common association we recorded was with morphine and pethidine., Conclusion: Our findings constitute the first step toward a more comprehensive evaluation of the clinical characteristics of DHRs in Lebanon., (© 2023 The Authors.)

Existing magnetic resonance imaging (MRI) reference objects, or phantoms, are typically constructed from simple liquid or gel solutions in containers with specific geometric configurations to enable multi-year stability. However, there is a need for phantoms that better mimic the human anatomy without barriers between the tissues. Barriers result in regions without MRI signal between the different tissue mimics, which is an artificial image artifact. We created an anatomically representative 3D structure of the brain that mimicked the T1 and T2 relaxation properties of white and gray matter at 3 T. While the goal was to avoid barriers between tissues, the 3D printed barrier between white and gray matter and other flaws in the construction were visible at 3 T. Stability measurements were made using a portable MRI system operating at 64 mT, and T2 relaxation time was stable from 0 to 22 weeks. The phantom T1 relaxation properties did change from 0 to 10 weeks; however, they did not substantially change between 10 weeks and 22 weeks. The anthropomorphic phantom used a dissolvable mold construction method to better mimic anatomy, which worked in small test objects. The construction process, though, had many challenges. We share this work with the hope that the community can build on our experience., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 + CD8 + T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 + CD8 + T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient's mutanome and immune microenvironment., (© 2023. The Author(s).)

The self-assembled skin substitute (SASS) is an autologous bilayered skin substitute designed by our academic laboratory, the Laboratoire d'Organogenèse Expérimentale (LOEX) to offer definitive treatment for patients lacking donor sites (unwounded skin) to cover their burn wounds. This product shows skin-like attributes, such as an autologous dermal and epidermal layer, and is easily manipulable by the surgeon. Its development stems from the need for skin replacement in high total body surface area burned survivors presenting few donor sites for standard split-thickness skin grafting. This review aims to present the history, successes, challenges, and current therapeutic indications of this skin substitute. We review the product's development history, before discussing current production techniques, as well as clinical use. The progression observed since the initial SASS production technique described in 1999, up to the most recent technique expresses significant advances made in the technical aspect of our product, such as the reduction of the production time. We then explore the efficacy and benefits of SASS over existing skin substitutes and discuss the outcomes of a recent study focusing on the successful treatment of 14 patients. Moreover, an ongoing cross-Canada study is further assessing the product's safety and efficacy. The limitations and technical challenges of SASS are also discussed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The aim of this preliminary study was to assess the impact of traumatic brain injury (TBI) in older age on executive functioning and on their functional outcome. We also aimed to explore the influence of cognitive reserve (CR) and estimated premorbid cognitive functioning (EPCF) on these components., Methods: A neuropsychological and functional assessment that included tests measuring Inhibition , Updating and Shifting, and functional outcome was administered to 29 patients who sustained a mild or moderate TBI in older age and a group of 24 healthy older participants. CR (level of education) and EPCF variables collected in the TBI group were associated with executive function performance and functional outcome., Results: Patients with TBI obtained significantly worse performances on the spatial working memory (WM) task-reverse condition, and on the completion time of the Trails A and B than the control group. The TBI group also obtained worse functional outcome scores. A higher level of education was associated with better WM performance, and higher estimated premorbid cognitive functioning was associated with better functional outcome post TBI., Conclusions: Further studies with a larger sample should be conducted to better understand the profile and determinants of recovery from TBI in the elderly.