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Purpose: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials., Methods and Materials: We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes., Results: Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART., Conclusions: This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphologic, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an AUC of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and posttreatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of patients with multiple myeloma, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and regulatory T cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of patients with multiple myeloma. In summary, deep learning-based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques., Significance: Spatial analysis of bone marrow trephine biopsies using histology, deep learning, and tailored algorithms reveals the bone marrow architectural heterogeneity and evolution during myeloma progression and treatment., (©2024 The Authors; Published by the American Association for Cancer Research.)

Metastasis is a nonrandom process with varying degrees of organotropism-specific source-acceptor seeding. Understanding how patterns between source and acceptor tumors emerge remains a challenge in oncology. We hypothesize that organotropism results from the macronutrient niche of cells in source and acceptor organs. To test this, we constructed and analyzed a metastatic network based on 9303 records across 28 tissue types. We found that the topology of the network is nested and modular with scale-free degree distributions, reflecting organotropism along a specificity/generality continuum. The variation in topology is significantly explained by the matching of metastatic cells to their stoichiometric niche. Specifically, successful metastases are associated with higher phosphorus content in the acceptor compared to the source organ, due to metabolic constraints in proliferation crucial to the invasion of new tissues. We conclude that metastases are codetermined by processes at source and acceptor organs, where phosphorus content is a limiting factor orchestrating tumor ecology.

Background: The Disability of the Arm, Shoulder and Hand (DASH) questionnaire assesses the impact of upper extremity disorders on quality of life. However, its use in the Mexican population has not been formally validated., Objective: To conduct a cultural adaptation and validation of the DASH questionnaire to evaluate the perspective of patients with neurogenic disorders of the upper extremity regarding the impact on their quality of life., Method: We performed an adaptation of the Spanish version of the DASH questionnaire to the Mexican vocabulary and applied it to 478 volunteers. Ceiling effect, floor effect, item-total correlation, descriptive statistics of items and total score, internal consistency, precision, cross-sectional and longitudinal validity were estimated by comparing healthy controls and affected individuals with different disability levels., Results: Our DASH questionnaire version was equivalent to those previously approved and showed homogeneity of the items with respect to the total value of the questionnaire (Cronbach's alpha > 0.96). In addition, it showed an accuracy of 7.25 points and the crosssectional and longitudinal validity was documented with significant differences between groups and subgroups with distinct disability levels., Conclusions: The DASH questionnaire can be used with a high level of confidence in the Mexican population.

Quiescence is a state of cell cycle arrest, allowing cancer cells to evade anti-proliferative cancer therapies. Quiescent cancer stem cells are thought to be responsible for treatment resistance in glioblastoma, an aggressive brain cancer with poor patient outcomes. However, the regulation of quiescence in glioblastoma cells involves a myriad of intrinsic and extrinsic mechanisms that are not fully understood. In this review, we synthesise the literature on quiescence regulatory mechanisms in the context of glioblastoma and propose an ecological perspective to stemness-like phenotypes anchored to the contemporary concepts of niche theory. From this perspective, the cell cycle regulation is multiscale and multidimensional, where the niche dimensions extend to extrinsic variables in the tumour microenvironment that shape cell fate. Within this conceptual framework and powered by ecological niche modelling, the discovery of microenvironmental variables related to hypoxia and mechanosignalling that modulate proliferative plasticity and intratumor immune activity may open new avenues for therapeutic targeting of emerging biological vulnerabilities in glioblastoma., Competing Interests: Declaration of Competing Interest The funders had no role in the writing of the manuscript, or the decision to submit the manuscript for publication. Y.Y. has received speakers bureau honoraria from Roche and consulted for Merck and Co Inc. The remaining authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum., Competing Interests: Declaration of interests H.H. is a co-founder of and equity holder in Omniscope, a scientific advisory board member of MiRXES, and a consultant to Moderna., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves = 2, and amphibia = 1), accuracy (range 0.57-0.94) is influenced by cell morphological similarity preserved across different taxonomic groups, tumour sites, and variations in the immune compartment. Furthermore, a spatial immune score based on artificial intelligence and spatial statistics is associated with prognosis in canine melanoma and prostate tumours. A metric, named morphospace overlap, is developed to guide veterinary pathologists towards rational deployment of this technology on new samples. This study provides the foundation and guidelines for transferring artificial intelligence technologies to veterinary pathology based on understanding of morphological conservation, which could vastly accelerate developments in veterinary medicine and comparative oncology., (© 2023. The Author(s).)

Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.

Cancer is a singular cellular state, the emergence of which destabilises the homeostasis reached through the evolution to multicellularity. We present the idea that the onset of the cellular disobedience to the metazoan functional and structural architecture, known as the cancer phenotype, is triggered by changes in the cell's external environment that occur with ageing: what ensues is a breach of the social contract of multicellular life characteristic of metazoans. By integrating old ideas with new evidence, we propose that with ageing the environmental information that maintains a multicellular organisation is eroded, rewiring internal processes of the cell, and resulting in an internal shift towards an ancestral condition resulting in the pseudo-multicellular cancer phenotype. Once that phenotype emerges, a new local social contract is built, different from the homeostatic one, leading to tumour formation and the foundation of a novel local ecosystem., (© 2020 Wiley Periodicals LLC.)

Objective: To describe the musculoskeletal disorders and association with physical and environmental in students of Dentistry., Methods: Cross sectional study. Simple random sampling was conducted obtaining a proportional sample of 182 students per semester. Collecting information from physical and environmental exposures related to different clinical practice and this was assessed by a structured survey questionnaire type. The valuation muscle was performed by visual analysis with Scan-test. To assess factors related to working position, the instrument was used RULA. For the analysis of the association were used odds ratios with confidence intervals of 95%. For the multivariate analysis using logistic regression., Results: 58.2% of students had pain tenderness in upper trapezius and 45.6% in area cervical. Lateral movements in the cervical found pain in 35.7%, with the bending cervical 35.1% related to all these factors own dental practice and not to other factors external., Conclusions: The onset of muscle pain in this population is influenced by multiple variables, most of them, related to dental practice of students to interact with each other can trigger symptoms at neck and back.

Animal venoms are rich sources of ligands for studying ion channels and other pharmacological targets. Proteomic analyses of the soluble venom from the Mexican scorpion Vaejovis mexicanus smithi showed that it contains more than 200 different components. Among them, a 36-residue peptide with a molecular mass of 3864 Da (named Vm24) was shown to be a potent blocker of Kv1.3 of human lymphocytes (K(d) ∼ 3 pM). The three-dimensional solution structure of Vm24 was determined by nuclear magnetic resonance, showing the peptide folds into a distorted cystine-stabilized α/β motif consisting of a single-turn α-helix and a three-stranded antiparallel β-sheet, stabilized by four disulfide bridges. The disulfide pairs are formed between Cys6 and Cys26, Cys12 and Cys31, Cys16 and Cys33, and Cys21 and Cys36. Sequence analyses identified Vm24 as the first example of a new subfamily of α-type K(+) channel blockers (systematic number α-KTx 23.1). Comparison with other Kv1.3 blockers isolated from scorpions suggests a number of structural features that could explain the remarkable affinity and specificity of Vm24 toward Kv1.3 channels of lymphocytes.

Mycobacterium tuberculosis catalase-peroxidase (KatG) is a bifunctional hemoprotein that has been shown to activate isoniazid (INH), a pro-drug that is integral to frontline antituberculosis treatments. The activated species, presumed to be an isonicotinoyl radical, couples to NAD(+)/NADH forming an isoniazid-NADH adduct that ultimately confers anti-tubercular activity. To better understand the mechanisms of isoniazid activation as well as the origins of KatG-derived INH-resistance, we have compared the catalytic properties (including the ability to form the INH-NADH adduct) of the wild-type enzyme to 23 KatG mutants which have been associated with isoniazid resistance in clinical M. tuberculosis isolates. Neither catalase nor peroxidase activities, the two inherent enzymatic functions of KatG, were found to correlate with isoniazid resistance. Furthermore, catalase function was lost in mutants which lacked the Met-Tyr-Trp crosslink, the biogenic cofactor in KatG which has been previously shown to be integral to this activity. The presence or absence of the crosslink itself, however, was also found to not correlate with INH resistance. The KatG resistance-conferring mutants were then assayed for their ability to generate the INH-NADH adduct in the presence of peroxide (t-BuOOH and H(2)O(2)), superoxide, and no exogenous oxidant (air-only background control). The results demonstrate that residue location plays a critical role in determining INH-resistance mechanisms associated with INH activation; however, different mutations at the same location can produce vastly different reactivities that are oxidant-specific. Furthermore, the data can be interpreted to suggest the presence of a second mechanism of INH-resistance that is not correlated with the formation of the INH-NADH adduct.

Tryptophan 2,3-dioxygenase (TDO), a liver-specific cytosolic hemoprotein, is the rate-limiting enzyme in L-tryptophan catabolism and thus a key serotonergic determinant. Glucocorticoids transcriptionally activate the TDO gene with marked enzyme induction. TDO is also regulated by heme, its prosthetic moiety, as its expression and function are significantly reduced after acute hepatic heme depletion. Here we show in primary rat hepatocytes that this impairment is not due to faulty transcriptional activation of the TDO gene but rather due to its posttranscriptional regulation by heme. Accordingly, in acutely heme-depleted hepatocytes, the de novo synthesis of TDO protein is markedly decreased (>90%) along with that of other hepatic proteins. This global suppression of de novo hepatic protein syntheses in these heme-depleted cells is associated with a significantly enhanced phosphorylation of the alpha-subunit of the eukaryotic initiation factor eIF2 (eIF2alpha), as monitored by the phosphorylated eIF2alpha/total eIF2alpha ratio. Heme supplementation reversed these effects, indicating that heme regulates TDO induction by functional control of an eIF2alpha kinase. A cDNA was cloned from heme-depleted rat hepatocytes, and DNA sequencing verified its identity to the previously cloned rat brain heme-regulated inhibitor (HRI). Proteomic, biochemical, and/or immunoblotting analyses of the purified recombinant protein and the immunoaffinity-captured hepatic protein confirmed its identity as a rat heme-sensitive eIF2alpha kinase. These findings not only document that a hepatic HRI exists and is physiologically relevant but also implicate its translational shut-off of key proteins in the pathogenesis and symptomatology of the acute hepatic heme-deficient conditions clinically known as the hepatic porphyrias.

The venom from the Brazilian scorpion Tityus stigmurus was fractionated by high performance liquid chromatography (HPLC) and the corresponding components were used for molecular mass determination using electrospray ion trap mass spectrometry. One hundred distinct components were clearly assigned showing molecular masses from 216.5 to 44,800.0 Da. Fifteen new components were isolated and sequenced, four of them to completion: Tst-3 (similar to Na(+) channel specific scorpion toxins), Tst-17 (a K(+) channel blocking peptide similar to Tc1), Tst beta KTx (a peptide with identical sequence as that of TsTX-K beta toxin earlier described to exist in T. serrulatus venom) and finally a novel proline-rich peptide of unknown function. Among the eleven components partially sequenced were two enzymes: hyaluronidase and lysozyme. The first enzyme has a molecular mass of 44,800.0 Da. This enzyme showed high activity against the substrate hyaluronan in vitro. Amino acid sequence of the second enzyme showed that it is similar to other known lysozymes, with similar molecular mass and sequence to that of bona fide lysozymes reported in public protein data banks. Finally, this communication reports a correlation among HPLC retention times and molecular masses of folded scorpion toxins as well as a comparative structural and physiological analysis of components from the venom of several species of the genus Tityus.