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Objective: The depth of invasion (DOI) is considered an independent risk factor for occult lymph node metastasis in oral cavity squamous cell carcinoma (OCSCC). It is used to decide whether an elective neck dissection (END) is indicated in the case of a clinically negative neck for early stage carcinoma (pT1/pT2). However, there is no consensus on the cut-off value of the DOI for performing an END. The aim of this study was to determine a cut-off value for clinical decision making on END, by assessing the association of the DOI and the risk of occult lymph node metastasis in early OCSCC. Methods: A retrospective cohort study was conducted at the Erasmus MC, University Medical Centre Rotterdam, The Netherlands. Patients surgically treated for pT1/pT2 OCSCC between 2006 and 2012 were included. For all cases, the DOI was measured according to the 8th edition of the American Joint Committee on Cancer guideline. Patient characteristics, tumor characteristics (pTN, differentiation grade, perineural invasion, and lymphovascular invasion), treatment modality (END or watchful waiting), and 5-year follow-up (local recurrence, regional recurrence, and distant metastasis) were obtained from patient files. Results: A total of 222 patients were included, 117 pT1 and 105 pT2. Occult lymph node metastasis was found in 39 of the 166 patients who received END. Univariate logistic regression analysis showed DOI to be a significant predictor for occult lymph node metastasis (odds ratio (OR) = 1.3 per mm DOI; 95% CI: 1.1–1.5, p = 0.001). At a DOI of 4.3 mm the risk of occult lymph node metastasis was >20% (all subsites combined). Conclusion: The DOI is a significant predictor for occult lymph node metastasis in early stage oral carcinoma. A NPV of 81% was found at a DOI cut-off value of 4 mm. Therefore, an END should be performed if the DOI is >4 mm. [ABSTRACT FROM AUTHOR]

Gaining insight into the mode of operation of heterogeneous catalysts is of great scientific and economic interest. Raman spectroscopy has proven its potential as a powerful vibrational spectroscopic technique for a fundamental and molecular-level characterization of catalysts and catalytic reactions. Raman spectra provide important insight into reaction mechanisms by revealing specific information on the catalysts' (defect) structure in the bulk and at the surface, as well as the presence of adsorbates and reaction intermediates. Modern Raman instrumentation based on single-stage spectrometers allows high throughput and versatility in design of in situ/operando cells to study working catalysts. This review highlights major advances in the use of Raman spectroscopy for the characterization of heterogeneous catalysts made during the past decade, including the development of new methods and potential directions of research for applying Raman spectroscopy to working catalysts. The main focus will be on gas–solid catalytic reactions, but (photo)catalytic reactions in the liquid phase will be touched on if it appears appropriate. The discussion begins with the main instrumentation now available for applying vibrational Raman spectroscopy to catalysis research, including in situ/operando cells for studying gas–solid catalytic processes. The focus then moves to the different types of information available from Raman spectra in the bulk and on the surface of solid catalysts, including adsorbates and surface depositions, as well as the use of theoretical calculations to facilitate band assignments and to describe (resonance) Raman effects. This is followed by a presentation of major developments in enhancing the Raman signal of heterogeneous catalysts by use of UV resonance Raman spectroscopy, surface-enhanced Raman spectroscopy (SERS), and shell-isolated nanoparticle surface-enhanced Raman spectroscopy (SHINERS). The application of time-resolved Raman studies to structural and kinetic characterization is then discussed. Finally, recent developments in spatially resolved Raman analysis of catalysts and catalytic processes are presented, including the use of coherent anti-Stokes Raman spectroscopy (CARS) and tip-enhanced Raman spectroscopy (TERS). The review concludes with an outlook on potential future developments and applications of Raman spectroscopy in heterogeneous catalysis. [ABSTRACT FROM AUTHOR]

Making human T cells see HIV-1: Cytomegalovirus (CMV)–based vaccines protect rhesus macaques from simian immunodeficiency virus infection by inducing atypical CD8+ T cell responses restricted to the rhesus HLA-E homolog. However, it is unclear whether these atypical CD8+ T cell responses might translate to human immunodeficiency virus (HIV) when using a vaccine based on a human CMV vector. Here, Yang et al. showed that HIV-1 Gag-specific, HLA-E–restricted CD8+ T cell clones could be generated in vitro from naïve T cells taken from HIV-1 uninfected people. These CD8+ T cell clones were able to suppress HIV-1–infected CD4+ target cells. These data indicate that HIV-1–specific, HLA-E–restricted CD8+ T cell clones can be generated in humans and that a human CMV vector–based vaccine for HIV may generate protective CD8+ T cell responses. Human leukocyte antigen-E (HLA-E) normally presents an HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (SIV) vaccine generated Mamu-E (HLA-E homolog)–restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, HIV-1–specific, HLA-E–restricted T cells have not been observed in HIV-1–infected individuals. Here, HLA-E–restricted, HIV-1–specific CD8+ T cells were primed in vitro. These T cell clones and allogeneic CD8+ T cells transduced with their T cell receptors suppressed HIV-1 replication in CD4+ T cells in vitro. Vaccine induction of efficacious HLA-E–restricted HIV-1–specific T cells should therefore be possible. [ABSTRACT FROM AUTHOR]

Cancer is the outcome of the conflict between the host immune system and cancer cells. The crosstalk between immune cells and tumor cells within the tumor microenvironment (TME) influences tumor progression and metastasis. Many studies have clarified the cellular and molecular events that can induce cancer cells to escape immune surveillance, including those involving tumor-induced myeloid cell-mediated immunosuppression. Emerging evidence indicates that tumor-infiltrating myeloid cells (TIMs) accelerate tumor growth and induce angiogenesis, metastasis, and therapy resistance once converted into potent immunosuppressive cells. Here, how tumor infiltrating myeloid cells participate in tumor immune evasion and the prospects of these cells in cancer immunotherapy are discussed. [ABSTRACT FROM AUTHOR]

The "Mendelian code" hypothesis postulates a relationship between Mendelian (monogenic) and common pathologies. In this hypothesis, polymorphisms in the genes of Mendelian diseases may have a significant contribution to predisposition to common diseases in which the same biochemical pathways may be involved. In this review a group of genes encoding various proteins participating in the DNA repair, with a particular focus on the BRCA1-associated genome surveillance complex (BASC), is presented through the prism of the "Mendelian code" hypothesis. Here we discuss (1) their main functions in the repair of DNA double-strand breaks (ATM, MRE11, NBN, RAD50, BRCA1, and BLM) and mismatch repair (MSH2, MSH6, MLH1, PMS2, RF-C, and PCNA); (2) the mitochondrial involvement of these proteins; (3) the involvement of BASC proteins in the development of an adaptive immune response. For 13 out of 16 BASC protein encoding genes, mutations leading to monogenic diseases have already been described; for 11, there are associations with common diseases or individual biological processes. Patients with mutations in the genes of the BASC complex and patients with severe combined immunodeficiency share similar symptoms. Polymorphisms within DNA repair genes may play a role in the development of common diseases through the involvement of the immune response. The pleiotropic effects of these genes suggest their participation in the development of various conditions, both in health and pathology. [ABSTRACT FROM AUTHOR]

Body composition (BC) characteristics across metabolic health-by-body mass index categories were examined. Metabolic health (MH) was defined by five biomarkers: waist circumference, blood pressure, levels of triglycerides, high density lipoprotein cholesterol, and fasting glucose. Potential differences in BC characteristics between metabolically healthy obese (MH-O) and metabolically unhealthy obese (MUH-O) women, and between MH normal weight (MH-NW) and MUH normal weight (MUH-NW) women were explored in 276 Slovak midlife women (39-65 years). Body composition parameters were measured with bioimpedance analyzer (BIA 101, Akern, S. r. l.). A simple comparison of the BC data between the subgroups showed significant differences in resistance (Rz, ohm) (p=0.035), muscle mass (MM, kg) (p=0.044), and total body water (TBW, kg) (p=0.047) between MH-O and MUH-O women. However, we did not observe any significant differences in BC characteristics between MH-NW and MUHNW. Specific logistic regression models were used to determine differences in BC characteristics between various obesity phenotypes, with controlling for age, menopausal status, smoking status and sport activity. Our results indicated that increasing age and decreasing Rz were statistically significantly associated with an increased likelihood of exhibiting MUH-O (p=0.031 for age; p=0.032 for Rz). Moreover, other logistic models which included age, menopausal status, biochemical variables and life style factors such as covariates, showed that increasing alanine aminotransferase (ALT) and uric acid (UA) were statistically significantly associated with an increased likelihood of exhibiting MUH-O (p=0.023 for ALT, p=0.010 for UA). In conclusion, MUH-O and MH-O cardiometabolic profiles are characterized by differences in the value of resistance and plasma levels of ALT and UA. [ABSTRACT FROM AUTHOR]

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The clinical application of antitumor immunotherapy still faces severe challenges related to efficacy. Here, a light‐triggered core–shell nanosystem is designed to boost antitumor immune response via controlled release of anti‐PD‐L1 (αPD‐L1) antibodies and enhanced antigen presentation. The nanosystem (AZ‐P@P) is constructed via integrating gold nanorods (AuNRs) as a photothermal core and zeolitic imidazolate framework‐8 (ZIF‐8) as a shell for aPD‐L1 delivery, and further PEGylating. In the nanosystem, the ZIF‐8 shell protects αPD‐L1 antibody from the complex physiological environment and hyperthermia. Once accumulated at the tumor site, AZ‐P@P under near‐infrared (NIR) light‐triggered heating induces tumor cell deaths releasing tumor‐derived protein antigens (TDPAs) and adenosine triphosphate (ATP). Thereafter, the released ATP degrades the ZIF‐8 shell to expose the AuNRs, which can promote intratumoral T cell infiltration by capturing TDPAs and transporting them to dendritic cells (DCs). Concurrently, a large amount of αPD‐L1 is released in situ to reinvigorate T cell activity. Mechanistic studies reveal that AZ‐P@P promotes the maturation of DCs and the infiltration of activated T cells, thus eliciting a robust antitumor immunity. It is demonstrated that AZ‐P@P triggered by NIR light can significantly destroy primary tumors and suppress metastasis. This multiple immunoregulatory system provides a promising tool for tumor treatment. [ABSTRACT FROM AUTHOR]

Purpose. Thyroid hormones play an important role in growth, development, and physiology of the kidney. The kidney plays a key role in the metabolism, degradation, and excretion of thyroid hormones and its metabolites. The aim of this study is to investigate the prevalence of disease states of thyroid-kidney organs and detecting the correlation between thyroid and kidney function abnormalities. Materials and Methods. In this retrospective study, a total of forty-five patients with thyroid and kidney dysfunction were investigated. Clinical features, laboratory data at initial presentation, management, and outcomes were collected. The paper has been written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. Median, percentage, mean ± standard deviation (SD), and the two-tailed t-test were used for statistical analyses. The correlation between variables was assessed by Pearson's, Spearman's correlation tests and regression analyses. Results. The mean ± SD of age of study patients was 48.2 ± 22.93 years (ranging from 1 to 90 years). There was no correlation between serum thyroid-stimulating hormone, free thyroxine levels with estimated glomerular filtration rate, and proteinuria. No association between antimicrosomal antibodies with estimated glomerular filtration rate was seen. Cardiovascular disease was the most common complication of overt hypothyroidism in kidney dysfunction patients. Conclusion. The present study showed more prevalence of primary hypothyroidism in comparison with other thyroid dysfunctions in patients with kidney dysfunction. Reduced mean values of thyroid function profiles after treatment suggest that this thyroid disease should be considered and ameliorated with thyroid hormone replacement therapy in patients with kidney disease. [ABSTRACT FROM AUTHOR]

The SDGs mark the clearest global acceptance yet that the previous approach to development was unsustainable. In VET, UNESCO has responded by developing a clear account of how a transformed VET must be part of a transformative approach to development. It argues that credible, comprehensive skills systems can be built that can support individuals, communities, and organisations to generate and maintain enhanced and just livelihood opportunities. However, the major current theoretical approaches to VET are not up to this challenge. In the context of Africa, we seek to address this problem through a presentation of literatures that contribute to the theorisation of this new vision. They agree that the world is not made up of atomised individuals guided by a "hidden hand". Rather, reality is heavily structured within political economies that have emerged out of contestations and compromises in specific historical and geographical spaces. Thus, labour markets and education and training systems have arisen, characterised by inequalities and exclusions. These specific forms profoundly influence individuals' and communities' views about the value of different forms of learning and working. However, they do not fully define what individuals dream, think and do. Rather, a transformed and transformative VET for Africa is possible. [ABSTRACT FROM AUTHOR]

How and to what extent electrical brain activity reflects pharmacologically altered states and contents of consciousness, is not well understood. Therefore, we investigated whether measures of evoked and spontaneous electroencephalographic (EEG) signal diversity are altered by sub-anaesthetic levels of ketamine compared to normal wakefulness, and how these measures relate to subjective experience. High-density 62-channel EEG was used to record spontaneous brain activity and responses evoked by transcranial magnetic stimulation (TMS) in 10 healthy volunteers before and during administration of sub-anaesthetic doses of ketamine in an open-label within-subject design. Evoked signal diversity was assessed using the perturbational complexity index (PCI), calculated from EEG responses to TMS perturbations. Signal diversity of spontaneous EEG, with eyes open and eyes closed, was assessed by Lempel Ziv complexity (LZc), amplitude coalition entropy (ACE), and synchrony coalition entropy (SCE). Although no significant difference was found in TMS-evoked complexity (PCI) between the sub-anaesthetic ketamine condition and normal wakefulness, all measures of spontaneous EEG signal diversity (LZc, ACE, SCE) showed significantly increased values in the sub-anaesthetic ketamine condition. This increase in signal diversity correlated with subjective assessment of altered states of consciousness. Moreover, spontaneous signal diversity was significantly higher when participants had eyes open compared to eyes closed, both during normal wakefulness and during influence of sub-anaesthetic ketamine. The results suggest that PCI and spontaneous signal diversity may reflect distinct, complementary aspects of changes in brain properties related to altered states of consciousness: the brain's capacity for information integration, assessed by PCI, might be indicative of the brain's ability to sustain consciousness, while spontaneous complexity, as measured by EEG signal diversity, may be indicative of the complexity of conscious content. Thus, sub-anaesthetic ketamine may increase the complexity of the conscious content and the brain activity underlying it, while the level or general capacity for consciousness remains largely unaffected. [ABSTRACT FROM AUTHOR]

Present work systematically investigates the kinetic role played by H2 molecules during Ni surface diffusion and deposition to generate branched Ni nanostructures by employing Density Functional Theory (DFT) calculations and ab initio molecule dynamic (AIMD) simulations, respectively. The Ni surface diffusion results unravel that in comparison to the scenarios of Ni(110) and Ni(100), both the subsurface and surface H hinder the Ni surface diffusion over Ni(111) especially under the surface H coverage of 1.5 ML displaying the lowest Ds values, which greatly favors the trapping of the adatom Ni and subsequent overgrowth along the 〈111〉 direction. The Ni deposition simulations by AIMD further suggest that both the H2 molecule (in solution) and surface dissociatively adsorbed atomic H can promote Ni depositions onto Ni(111) and Ni(110) facets in a liquid solution. Moreover, a cooperation effect between H2 molecules and surface atomic H can be clearly observed, which greatly favors Ni depositions. Additionally, in addition to working as the solvent, the liquid C2H5OH can also interact with the Ni(111) surface to produce the surface atomic H, which then favored the Ni deposition. Finally, the Ni deposition rate predicted using the deposition constant (Ddep) was found to be much higher than its surface diffusion rate predicted using Ds for Ni(111) and Ni(110), which quantitatively verified the overgrowth along the 〈111〉 and 〈110〉 directions to produce the branched Ni nanostructures. [ABSTRACT FROM AUTHOR]

Dysfunctional DNA repair with subsequent genome instability and high mutational burden represents a major hallmark of cancer. In established malignant tumors, increased DNA repair capacity mediates resistance to DNA-damaging therapeutics, including cytotoxic drugs, radiotherapy, and selected small molecules including inhibitors of poly (ADP-ribose) polymerase (PARP), Ataxia Telangiectasia Mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR), and Wee1 kinase (Wee1). In addition, DNA repair deficiency is not only associated with sensitivity to selected anticancer drugs, but also with increased mutagenicity and increased neoantigen load on tumor cells, resulting in increased immunogenicity and improved response to CTLA4- or PD-(L)1 targeting monoclonal antibodies. DNA damage response (DDR) is composed of complex signalling pathways, including the sensing of the DNA damage, signal transduction, cellular response pathways to DNA damage, and activation of DNA repair. DNA double strand breaks (DSBs) are the most dangerous form of DNA damage. Tumor cells are characterised by frequent accumulation of DSBs caused by either endogenous replication stress or the impact of cancer treatment, most prominently chemotherapy and radiotherapy. Therefore, response of cancer cells to DSBs represents a crucial mechanism for how tumors respond to systemic treatment or radiotherapy, and how resistance develops. Ample clinical evidence supports the importance of DDR associated kinases as predictive and prognostic biomarkers in cancer patients. The ATM-CHK2 and ATR-CHK1-WEE1 pathways initiate DNA DSB repair. In the current review, we focus on major DDR associated kinases including ATM, ATR, CHK1, CHK2, and WEE1, and discuss their potential prognostic and predictive value in solid malignancies. [ABSTRACT FROM AUTHOR]

Recent advances have redefined a role for T cell factor 1 (TCF1) that goes beyond T cell development and T memory formation and encompasses new functions in the regulation of T cell biology. Here, we discuss the multifaceted and context-dependent role of TCF1 in peripheral T cells, particularly during disease-induced inflammatory states such as autoimmunity, cancer, and chronic infections. Understanding how TCF1 fine-tunes peripheral T cell biology holds the potential to tailor improved immune-targeted therapies. [ABSTRACT FROM AUTHOR]

The rapidly evolving field of immunotherapy has attracted great attention in the field of cancer research and already revolutionized the clinical practice standard for treating cancer. Genetically engineered T cells expressing either T cell receptors or chimeric antigen receptors represent novel treatment modalities and are considered powerful weapons to fight cancer. The immune checkpoint blockade, which harnesses the negative control signaling behind the anti‐tumor immune response with therapeutic antibodies by blocking cytotoxic T lymphocyte‐associated protein 4 or the programmed cell death 1 pathways are another mainstream direction for cancer immunotherapy. In addition to cytotoxic T cells, other immune cell types such as nature killer cells and macrophages also possess the ability to eradicate cancer cells, which may serve as the basis to develop novel cancer immunotherapies. The advent of cutting‐edge genome editing technology, especially clustered regularly interspaced palindromic repeats (CRISPR)‐based tools, has greatly expedited many biomedical research areas, including cancer immunology and immunotherapy. In this review, the contribution of current CRISPR techniques to basic and translational cancer immunology research is discussed, and the future for cancer immunotherapy in the age of CRISPR is predicted. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can improve the clinical outcomes of chemo‐immunotherapeutic combination regimens through the establishment of a long‐term cancer immunity. None of the clinically used DNA‐binding PtII complexes is considered a Type II ICD inducer. We generated a series of PtII‐carbene complexes by applying minor structural alterations to the scaffold of a Type II ICD inducer Pt‐NHC and compared their efficiency in triggering ICD‐related cellular responses and phagocytosis. We successfully identified PlatinER, a novel highly potent PtII candidate with superior ICD properties. Crucially, the magnitude of ICD‐associated phagocytosis induced upon exposure of cancer cells to Pt complexes was dependent on the levels of ER‐localized reactive oxygen species (ROS) generation, which underpins their mechanisms of action and provides a feasible approach for the design of more effective Type II ICD inducers. [ABSTRACT FROM AUTHOR]

Immunotherapy is a class of promising anticancer treatments that has recently gained attention due to surging numbers of FDA approvals and extensive preclinical studies demonstrating efficacy. Nevertheless, further clinical implementation has been limited by high variability in patient response to different immunotherapeutic agents. These treatments currently do not have reliable predictors of efficacy and may lead to side effects. The future development of additional immunotherapy options and the prediction of patient‐specific response to treatment require advanced screening platforms associated with accurate and rapid data interpretation. Advanced engineering approaches ranging from sequencing and gene editing, to tumor organoids engineering, bioprinted tissues, and organs‐on‐a‐chip systems facilitate the screening of cancer immunotherapies by recreating the intrinsic and extrinsic features of a tumor and its microenvironment. High‐throughput platform development and progress in artificial intelligence can also improve the efficiency and accuracy of screening methods. Here, these engineering approaches in screening cancer immunotherapies are highlighted, and a discussion of the future perspectives and challenges associated with these emerging fields to further advance the clinical use of state‐of‐the‐art cancer immunotherapies are provided. [ABSTRACT FROM AUTHOR]

Objective: To define the human papillomavirus (HPV) subtypes seen in a large adult population with traditionally defined recurrent respiratory papillomatosis.Study Design: Retrospective review.Setting: Tertiary care laryngology practice.Subjects and Methods: All patients had a firm diagnosis of recurrent respiratory papillomatosis defined by (1) visually obvious papillomas, (2) recurrence requiring multiple surgeries, and (3) pathology diagnosis of "papilloma." Each patient had also undergone HPV subtyping. Age, sex, presence of malignancy, and HPV subtypes were tabulated and correlated with long-term patient outcomes.Results: A total of 184 patients were identified who fulfilled the above criteria. In total, 87.0% (160) had a low risk subtype; 9.2% had an alternative subtype. These consisted of subtypes 16, 18, 31, 44, 45, 55, and 70. Four patients (2.2%) had combinations of subtypes, with 1 patient with HPV 11 and 16, 1 patient with HPV 11 and 76, 1 patient with 11 and 84, and 1 patient with 18 and 45. Finally, 3.8% of patients were HPV negative, despite fulfilling all 3 criteria listed above.Conclusion: In the patient population above, almost 10% of patients had an HPV subtype other than 6 and 11. This suggests that traditionally defined recurrent respiratory papillomatosis (RRP) can be caused by HPV subtypes other than 6 and/or 11. In addition, the clinical course of persons with this definition of RRP appears to vary by subtype, and this information may offer the ability to nuance follow-up instructions, reducing in particular the burden placed upon patients who have RRP caused by subtypes 6 and 11. [ABSTRACT FROM AUTHOR]

Event‐related potentials (ERPs) are used extensively to investigate the neural mechanisms of attention control and selection. The univariate ERP approach, however, has left important questions inadequately answered. We addressed two questions by applying multivariate pattern classification to multichannel ERPs in two cued visual spatial attention experiments (N = 56): (a) impact of cueing strategies (instructional vs. probabilistic) on attention control and selection and (b) neural and behavioral effects of individual differences. Following cue onset, the decoding accuracy (cue left vs. cue right) began to rise above chance level earlier and remained higher in instructional cueing (~80 ms) than in probabilistic cueing (~160 ms), suggesting that unilateral attention focus leads to earlier and more distinct formation of the attention control set. A similar temporal sequence was also found for target‐related processing (cued target vs. uncued target), suggesting earlier and stronger attention selection under instructional cueing. Across the two experiments: (a) individuals with higher cue‐related decoding accuracy showed higher magnitude of attentional modulation of target‐evoked N1 amplitude, suggesting that better formation of anticipatory attentional state leads to stronger modulation of target processing, and (b) individuals with higher target‐related decoding accuracy showed faster reaction times (or larger cueing effects), suggesting that stronger selection of task‐relevant information leads to better behavioral performance. Taken together, multichannel ERPs combined with machine learning decoding yields new insights into attention control and selection that complement the univariate ERP approach, and along with the univariate ERP approach, provides a more comprehensive methodology to the study of visual spatial attention. [ABSTRACT FROM AUTHOR]

Perturb and observe screening in haploid cells: Yeast have been a powerful model organism for genetic screens because they can easily be genetically manipulated during the haploid portion of their life cycle. De Zan et al. used a quantitative genetic screen in the HAP1 haploid human cell line that generated reproducible results in different laboratories without explicit standardization. The authors used this screening approach to identify genes whose loss of function by mutation increased or decreased the phosphorylation of ribosomal protein S6 (RPS6), a measure of the activity of mTORC1, a complex that mediates responses to nutrient availability. Adding pharmacological or genetic perturbations to the screen showed that LAMTOR4 enhanced the inhibition of mTORC1 by rapamycin, an effect not demonstrated by the related LAMTOR5, and that LAMTOR4 had a synthetic sick/lethal interaction with folliculin. This approach has the potential to reveal regulators of signaling pathways that function in specific contexts. Forward genetic screens in mammalian cell lines, such as RNAi and CRISPR-Cas9 screens, have made major contributions to the elucidation of diverse signaling pathways. Here, we exploited human haploid cells as a robust comparative screening platform and report a set of quantitative forward genetic screens for identifying regulatory mechanisms of mTORC1 signaling, a key growth control pathway that senses diverse metabolic states. Selected chemical and genetic perturbations in this screening platform, including rapamycin treatment and genetic ablation of the Ragulator subunit LAMTOR4, revealed the known core mTORC1 regulatory signaling complexes and the intimate interplay of the mTORC1 pathway with lysosomal function, validating the approach. In addition, we identified a differential requirement for LAMTOR4 and LAMTOR5 in regulating the mTORC1 pathway under fed and starved conditions. Furthermore, we uncovered a previously unknown "synthetic-sick" interaction between the tumor suppressor folliculin and LAMTOR4, which may have therapeutic implications in cancer treatment. Together, our study demonstrates the use of iterative "perturb and observe" genetic screens to uncover regulatory mechanisms driving complex mammalian signaling networks. [ABSTRACT FROM AUTHOR]

All roads lead to antitumor immunity: Immune checkpoint blockade immunotherapy for cancer has been achieving increasing prominence in recent years, but, unfortunately, it still only works for a subset of patients and tumor types. Wang et al. found that higher expression of lysine demethylase KDM5A in tumors correlates with their responses to immune checkpoint inhibition. The authors then found a way to take advantage of this mechanism using a compound that increased both KDM5A and a key immune checkpoint protein. At the same time, this compound also activated Toll-like receptor signaling, further stimulating antitumor immunity in multiple mouse models. Immune checkpoint blockade (ICB) therapies are now established as first-line treatments for multiple cancers, but many patients do not derive long-term benefit from ICB. Here, we report that increased amounts of histone 3 lysine 4 demethylase KDM5A in tumors markedly improved response to the treatment with the programmed cell death protein 1 (PD-1) antibody in mouse cancer models. In a screen for molecules that increased KDM5A abundance, we identified one (D18) that increased the efficacy of various ICB agents in three murine cancer models when used as a combination therapy. D18 potentiated ICB efficacy through two orthogonal mechanisms: (i) increasing KDM5A abundance, which suppressed expression of the gene PTEN (encoding phosphatase and tensin homolog) and increased programmed cell death ligand 1 abundance through a pathway involving PI3K-AKT-S6K1, and (ii) activating Toll-like receptors 7 and 8 (TLR7/8) signaling pathways. Combination treatment increased T cell activation and expansion, CD103+ tumor-infiltrating dendritic cells, and tumor-associated M1 macrophages, ultimately enhancing the overall recruitment of activated CD8+ T cells to tumors. In patients with melanoma, a high KDM5A gene signature correlated with KDM5A expression and could potentially serve as a marker of response to anti–PD-1 immunotherapy. Furthermore, our results indicated that bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents. [ABSTRACT FROM AUTHOR]

A deeper look at cancer immunity: A key goal in oncology is diagnosing cancer early, when it is more treatable. Despite decades of progress, early diagnosis of asymptomatic patients remains a major challenge. Most methods for this involve detecting cancer cells or their DNA, but Beshnova et al. suggested a different approach, focused on the body's immune response. The authors reasoned that the presence of cancer may cause alterations in the T cell receptor repertoire, which could then be detected. They designed a deep learning method for distinguishing the T cell repertoires in the blood of patients with and without cancer, which they validated in samples from multiple clinical cohorts. The adaptive immune system recognizes tumor antigens at an early stage to eradicate cancer cells. This process is accompanied by systemic proliferation of the tumor antigen–specific T lymphocytes. While detection of asymptomatic early-stage cancers is challenging due to small tumor size and limited somatic alterations, tracking peripheral T cell repertoire changes may provide an attractive solution to cancer diagnosis. Here, we developed a deep learning method called DeepCAT to enable de novo prediction of cancer-associated T cell receptors (TCRs). We validated DeepCAT using cancer-specific or non-cancer TCRs obtained from multiple major histocompatibility complex I (MHC-I) multimer-sorting experiments and demonstrated its prediction power for TCRs specific to cancer antigens. We blindly applied DeepCAT to distinguish over 250 patients with cancer from over 600 healthy individuals using blood TCR sequences and observed high prediction accuracy, with area under the curve (AUC) ≥ 0.95 for multiple early-stage cancers. This work sets the stage for using the peripheral blood TCR repertoire for noninvasive cancer detection. [ABSTRACT FROM AUTHOR]

Background: The CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) is a key regulator of the programed death receptor ligand-1 (PD-L1) protein. However, the usefulness of CMTM6 expression as a prognostic indicator and the relationship between CMTM6 and PD-L1 expression in gastric cancer (GC) remains unclear. Objectives: We evaluated the expression and prognostic implications of CMTM6 in GC tissue and its relationship with PD-L1 expression. Patients and methods: The protein expressions of CMTM6 and PD-L1 were detected in 122 cases of postoperative GC tissue using immunohistochemical (IHC) assays. Kaplan-Meier survival analysis was used to calculate the survival probability and a log-rank test was used to compare the survival curves. Univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the clinically-related factors associated with survival. Pearson's correlation was used to determine the correlation analysis and estimate the statistical significance. The univariate and multivariate logistic regression analyses were used to analyze the relationship between clinically-related factors and PD-L1 expression. Results: Kaplan-Meier survival analysis showed that patients with high CMTM6 expression had shorter overall survival (OS) than those with low expression (P < 0.001). The expression of CMTM6 was an independent risk factor for prognosis in multivariate Cox proportional hazard regression analyses (HR:2.221, CI% [1.36-3.628], P = 0.001). The OS of patients with positively expressed PD-L1 was significantly shorter than those with negatively expressed PD-L1 (P = 0.003). The expression of CMTM6 was significantly related to the positive expression of PD- L1 in gastric cancer tissues (r = 0.186, P = 0.041). The expression of CMTM6 was the independent risk factor for PD-L1 expression in multivariate logistic regression analysis (OR:2.538, CI% [1.128-5.714], P = 0.024). Conclusion: CMTM6 expression is significantly related to PD-L1 and may be a useful prognostic indicator and a specific therapeutic target for cancer immunotherapy for GC patients. [ABSTRACT FROM AUTHOR]

Patients with triple negative breast cancer (TNBC) typically receive chemotherapy, surgery, and radiation therapy. Although this treatment improves prognosis for most patients, some patients continue to experience recurrence within 5 years. Preclinical studies have shown that immune cell infiltration at the irradiated site may play a significant role in tumor cell recruitment; however, little is known about the mechanisms that govern this process. This lack of knowledge highlights the need to evaluate radiation-induced cell infiltration with models that have controllable variables and maintain biological integrity. Mammary organoids are multicellular three-dimensional (3D) in vitro models, and they have been used to examine many aspects of mammary development and tumorigenesis. Organoids are also emerging as a powerful tool to investigate normal tissue radiation damage. In this review, we evaluate recent advances in mammary organoid technology, consider the advantages of using organoids to study radiation response, and discuss future directions for the applications of this technique. [ABSTRACT FROM AUTHOR]

We present full water depth sections of size‐fractionated (1–51 μm; >51 μm) concentrations of suspended particulate matter and major particle phase composition (particulate organic matter [POM], including its carbon isotopic composition [POC‐δ13C] and C:N ratio, calcium carbonate [CaCO3], opal, lithogenic particles, and iron and manganese [oxyhydr]oxides) from the U.S. GEOTRACES Arctic Cruise (GN01) in the western Arctic in 2015. Whereas biogenic particles (POM and opal) dominate the upper 1,000 m, lithogenic particles are the most abundant particle type at depth. Minor phases such as manganese (Mn) oxides are higher in GN01 than in any other U.S. GEOTRACES cruises so far. Extremely depleted POC‐δ13C, as low as ~ −32‰, is ubiquitous at the surface of the western Arctic Ocean as a result of different growth rates of phytoplankton. Moderate penetration of depleted POC‐δ13C to depth indicates active sinking of large particles in the central basin. Lateral transport from the Chukchi shelf is also of significance in the western Arctic, as is evident from increases in biogenic silica to POC ratios and Mn oxide concentrations in the halocline, as well as lithogenic element contents in the deep waters. Our study supports previous suggestions of the near absence of CaCO3 in the Arctic Basin. This study presents the first data set of concentration and composition of suspended particles in the western Arctic Ocean and sheds new light on the vertical and lateral processes that govern particle distribution in this enclosed ocean basin. Plain Language Summary: A comprehensive investigation of distributions and characteristics of marine particles in the western Arctic Ocean was conducted in 2015. Factors that make the Arctic Ocean unique, such as cold temperatures, freshwater inputs from surrounding rivers, and the continentally enclosed nature of this ocean basin, also lead to unique chemical compositions of its suspended particles. The contrasting chemical compositions of particles from a highly productive coastal region compared to particles from a low‐productivity central Arctic Basin allows them to be used as chemical fingerprints for tracing horizontal versus vertical transport in the water column. This information may help further understand sources and transport mechanisms of particles in the Arctic Ocean as climate change fundamentally alters the Arctic Ocean. Key Points: Particle composition in Chukchi shelf is distinct from Arctic Basin; differences are used to discern lateral from vertical particle transportThe importance of lateral transport can be traced by high Si:C and manganese oxides in the halocline and lithogenic particles in the deepAlthough large particle abundance is low, their sinking is evident given the very depleted carbon isotopic signatures in the subsurface [ABSTRACT FROM AUTHOR]

Metacognitive awareness—the ability to know that one is having a particular experience—is thought to guide optimal behavior, but its neural bases continue to be the subject of vigorous debate. Prior work has identified correlations between perceptual metacognitive ability and the structure and function of lateral prefrontal cortex (LPFC); however, evidence for a causal role of this region in promoting metacognition is controversial. Moreover, whether LPFC function promotes metacognitive awareness of perceptual and emotional features of complex, yet ubiquitous face stimuli is unknown. Here, using model-based analyses following a causal intervention to LPFC in humans, we demonstrate that LPFC function promotes metacognitive awareness of the orientation of faces—although not of their emotional expressions. Collectively, these data support the causal involvement of the prefrontal cortex in metacognitive awareness, and indicate that the role of LPFC in metacognition encompasses perceptual experiences of naturalistic social stimuli. Regina C. Lapate et al. study the role of lateral prefrontal cortex (LPFC) in metacognitive awareness in humans. They use transcranial magnetic stimulation, emotional face stimuli and model-based analyses to demonstrate that LPFC function promotes metacognitive awareness of the orientation, but not the emotional expression, of human faces. [ABSTRACT FROM AUTHOR]

Background : The principal aim of this study was to measure the effect of online single-pulse transcranial magnetic stimulation (TMS) over the right dorsolateral prefrontal cortex (DLPFC) on cognition via the Cambridge Neuropsychological Test Automated Battery (CANTAB) in healthy individuals. Methods : In a single-blind, sham-controlled study, we assessed both 50% and 60% of the resting motor threshold (RMT) over the right DLPFC in healthy right-handed (n = 42) adults using cognitive function, such as attention and memory, as a measure via CANTAB. Results : We observed an improvement in the cognitive function level during the use of online low intensities of 50% and 60% RMT active stimulation of the DLPFC compared to the sham stimulation. Conclusions : The results showed that low-intensity TMS can indeed effectively modulate cognitive function in DLPFC. Future research is, however, necessary to investigate the potential effects of low-intensity TMS on different brain areas to increase confidence in the observed results. [ABSTRACT FROM AUTHOR]

Background: Obesity does not always lead to non-communicable diseases. The objective of this paper is to estimate the prevalence of obese and disease-free population among Malaysian adult aged 18 years and above and to determine the lifestyle and dietary factors on this population. Materials and Methods: Data from the Malaysia National Health and Morbidity Survey (NHMS) 2015, a cross sectional design, applied two stage stratified cluster sampling. Obese and disease-free population was defined as population of obese adults with no known diagnosis of diabetes, hypertension, and high cholesterol. Descriptive analysis of the background characteristics was performed and complex sampling was used to determine the prevalence of obese and disease-free population. Multiple logistic regression was used to determine factors associated with obese and disease free. Data was analysed using SPSS version 25.A p-value of <0.05 was considered significant. Result: 23.7% of Malaysian adults were obese and disease free. Multivariate analysis showed there were no association between lifestyle determinants (physical activity, smoking and alcohol) and dietary factors (fruits and vegetables intake) on these population. Significant associations were revealed among adults aged 18-24 [aOR: 5.00 (95% CI3.22-7.73)] and 25-44 years old [aOR: 2.45(95%CI 1.65-3.64)]. The Nagelkerke R Square analysis predicted that with each passing year, the probability of these population becoming unhealthy obesity increases by 4.4%. Conclusion: Obese and disease-free population is present among obese population. No significant association was reported for lifestyle determinants and dietary factors on these population. A focus shift on parameters of metabolic health should be considered. [ABSTRACT FROM AUTHOR]

Background: The choice of treatment in laryngeal cancer is mainly based on tumor stage, post‐treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance. Objective of the review: The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy. Type of Review: Systematic review. Search strategy: PubMed, Embase, Cochrane Library. Evaluation Method: A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers. Results: A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki‐67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX‐2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy. Conclusions: Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy. [ABSTRACT FROM AUTHOR]

In this paper, two researchers reflect on the institutional space for participatory governance in a participatory action research (PAR) process that was initiated by the Ministry of Education, Culture and Science (ECS) in the Netherlands. It was implemented in two schools by researchers contracted by the ministry. The project's aim was to explore possibilities for involving schools in policy processes using PAR. We conclude that PAR sheds light on the communication strategies, power and authority balances, and meaning of participation among the participants. The attempt to break through traditional hierarchies generated new insights into the institutional space at both the participating schools and the government institutions that can be used to create participatory approaches to governance. The researchers were the bridging actors between the schools and the government institutions. While previous research showed that a bridging actor can play a positive role as an objective party who is able to deliberate between the participants, we found that it impeded the creation of a participatory governance space. [ABSTRACT FROM AUTHOR]

AMPing up cytotoxicity: Cytotoxic T cells (CTLs) form an immune synapse at the interface formed with their target cells and then reorient intracellular lytic granules toward the contact site to ensure efficient killing. Zurli et al. found that stimulation of the receptor CD2 on CTLs by CD58 on target B cells enhanced T cell receptor signaling during immune synapse formation. Phosphoproteomics analysis showed that CD2 stimulation led to activation of the metabolism-regulating kinase AMPK on lysosomes, which promoted lytic granule translocation to the immune synapse. Together, these findings suggest that targeting the CD2-AMPK axis may enhance CTL activity. Understanding the costimulatory signaling that enhances the activity of cytotoxic T cells (CTLs) could identify potential targets for immunotherapy. Here, we report that CD2 costimulation plays a critical role in target cell killing by freshly isolated human CD8+ T cells, which represent a challenging but valuable model to gain insight into CTL biology. We found that CD2 stimulation critically enhanced signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules toward the microtubule-organizing center (MTOC). To gain insight into the underlying mechanism, we explored the CD2 signaling network by phosphoproteomics, which revealed 616 CD2-regulated phosphorylation events in 373 proteins implicated in the regulation of vesicular trafficking, cytoskeletal organization, autophagy, and metabolism. Signaling by the master metabolic regulator AMP-activated protein kinase (AMPK) was a critical node in the CD2 network, which promoted granule polarization toward the MTOC in CD8+ T cells. Granule trafficking was driven by active AMPK enriched on adjacent lysosomes, revealing previously uncharacterized signaling cross-talk between vesicular compartments in CD8+ T cells. Our results thus establish CD2 signaling as key for mediating cytotoxic killing and granule polarization in freshly isolated CD8+ T cells and strengthen the rationale to choose CD2 and AMPK as therapeutic targets to enhance CTL activity. [ABSTRACT FROM AUTHOR]

Cancer is one of the deadliest diseases worldwide. Recent statistics have shown that metastases and tumor relapse are the leading causes of cancer-associated deaths. While traditional treatments are able to efficiently remove the primary tumor, secondary tumors remain poorly accessible. Capitalizing on this there is an urgent need for novel treatment modalities. Among the most promising approaches, increasing research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Preliminary studies have shown that immunogenic cell death inducing compounds could be able to overcome metastatic and relapsing tumors. Herein, the application of metal complexes as immunogenic cell death inducing compounds is systematically reviewed., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Harnessing innate immunity is an appealing strategy for cancer treatment. Herein, we report a new strategy called molecularly imprinted nanobeacons (MINBs) for redirecting innate immune killing towards triple-negative breast cancer (TNBC). The MINBs were molecularly imprinted nanoparticles with the N-epitope of glycoprotein nonmetastatic B (GPNMB) as the template and grafted with plentiful fluorescein moieties as the hapten. The MINBs could tag the TNBC cells via binding with GPNMB and thereby provide navigation for recruiting hapten-specific antibodies. The gathered antibodies could further trigger effective Fc-domain-mediated immune killing towards the tagged cancer cells. In vivo experiments showed that the TNBC growth was significantly inhibited after MINBs treatment by intravenous injection as compared with control groups. This study not only opens a new access for redirecting innate immunity towards TNBC but also paves the way for innate immunity-based therapy of other diseases., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

This review focuses on reports that link music training to working memory and neural oscillations. Music training is increasingly associated with improvement in working memory, which is strongly related to both localized and distributed patterns of neural oscillations. Importantly, there is a small but growing number of reports of relationships between music training, working memory, and neural oscillations in adults. Taken together, these studies make important contributions to our understanding of the neural mechanisms that support effects of music training on behavioral measures of executive functions. In addition, they reveal gaps in our knowledge that hold promise for further investigation. The current review is divided into the main sections that follow: (1) discussion of behavioral measures of working memory, and effects of music training on working memory in adults; (2) relationships between music training and neural oscillations during temporal stages of working memory; (3) relationships between music training and working memory in children; (4) relationships between music training and working memory in older adults; and (5) effects of entrainment of neural oscillations on cognitive processing. We conclude that the study of neural oscillations is proving useful in elucidating the neural mechanisms of relationships between music training and the temporal stages of working memory. Moreover, a lifespan approach to these studies will likely reveal strategies to improve and maintain executive function during development and aging. [ABSTRACT FROM AUTHOR]

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (Tregs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy. [ABSTRACT FROM AUTHOR]

Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Finally, we survey cutting-edge research in therapeutic circuit modulation using novel paradigms and next-generation devices. [ABSTRACT FROM AUTHOR]

This work reviews the state‐of‐the‐art models for the simulation of bubble columns and focuses on methods coupled with computational fluid dynamics (CFD) where the potential and deficits of the models are evaluated. Particular attention is paid to different approaches in multiphase fluid dynamics including the population balance to determine bubble size distributions and the modeling of turbulence where the authors refer to numerous published examples. Additional models for reactive systems are presented as well as a special chapter regarding the extension of the models for the simulation of bubble columns with a present solid particle phase, i.e., slurry bubble columns. [ABSTRACT FROM AUTHOR]

The catalytic reduction of aromatic nitro compounds with hydrogen was carried out for the first time over low-temperature copper hydrosilicates synthesized at 92–110 °C as catalysts. Copper hydrosilicates demonstrated high catalytic activity and selectivity towards nitrobenzene hydrogenation to aniline and p-dinitrobenzene hydrogenation to p-nitroaniline and p-phenylenediamine under relatively mild conditions (150–170 °C, hydrogen pressure of 1.3 MPa). [ABSTRACT FROM AUTHOR]

Dishing out treatment recommendations: The number of treatment options for cancer patients keeps expanding, but it remains difficult to predict which tumors will be sensitive to which treatments. As a result, most patients receive treatment according to standardized protocols. With this approach, some patients respond to treatment, but others only experience side effects. To help address this situation, Ooft et al. developed a method of testing drugs in patient-derived organoids, biopsy-derived cells from individual patients grown in a dish. In a clinical study, the responses of organoids to irinotecan correlated with patients' responses to the drug, suggesting that organoids could help avoid giving irinotecan to patients who would not benefit. There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy. [ABSTRACT FROM AUTHOR]

γδ T cells: Guarding and defending tissues Specific γδ T cell subsets are known to populate tissues such as the skin and gut. To ascertain γδ T cell participation in breast cancer surveillance, Wu et al. isolated cells from grid cultures of human breast tissue. They observed cytolytic innate-like Vδ1+ T cells in healthy human breast tissue as well as tumor tissue. Analysis of a small cohort of women with triple-negative breast cancer revealed that these Vδ1+ T cells were associated with remission and overall survival. These results demonstrate that human tissue-resident γδ T cells may affect breast cancer progression; these cells could be key to existing or future immunotherapy interventions. Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells. [ABSTRACT FROM AUTHOR]

Objectives: Noninvasive brain stimulation methods, including high-definition transcranial direct current stimulation (HD-tDCS) and theta burst stimulation (TBS) have emerged as novel tools to modulate and explore brain function. However, the relative efficacy of these newer stimulation approaches for modulating cognitive functioning remains unclear. This study investigated the cognitive effects of HD-tDCS, intermittent TBS (iTBS) and prolonged continuous TBS (ProcTBS) and explored the potential of these approaches for modulating hypothesized functions of the left posterior parietal cortex (PPC). Methods: Twenty-two healthy volunteers attended four experimental sessions in a cross-over experimental design. In each session, participants either received HD-tDCS, iTBS, ProcTBS or sham, and completed cognitive tasks, including a divided attention task, a working memory maintenance task and an attention task (emotional Stroop test). Results: The results showed that compared to sham, HD-tDCS, iTBS and ProcTBS caused significantly faster response times on the emotional Stroop task. The effect size (Cohen's d) was d =.32 for iTBS (p <.001),.21 for ProcTBS (p =.01) and.15 for HD-tDCS (p =.044). However, for the performance on the divided attention and working memory maintenance tasks, no significant effect of stimulation was found. Conclusions: The results suggest that repetitive transcranial magnetic stimulation techniques, including TBS, may have greater efficacy for modulating cognition compared with HD-tDCS, and extend existing knowledge about specific functions of the left PPC. [ABSTRACT FROM AUTHOR]

Targeted stimulation can be used to modulate the activity of brain networks. Previously we demonstrated that direct electrical stimulation produces predictable poststimulation changes in brain excitability. However, understanding the neural dynamics during stimulation and its relationship to poststimulation effects is limited but critical for treatment optimization. Here, we applied 10 Hz direct electrical stimulation across several cortical regions in 14 human subjects (6 males) implanted with intracranial electrodes for seizure monitoring. The stimulation train was characterized by a consistent increase in high gamma (70–170 Hz) power. Immediately post-train, low-frequency (1–8 Hz) power increased, resulting in an evoked response that was highly correlated with the neural response during stimulation. Using two measures of network connectivity, corticocortical evoked potentials (indexing effective connectivity), and theta coherence (indexing functional connectivity), we found a stronger response to stimulation in regions that were highly connected to the stimulation site. In these regions, repeated cycles of stimulation trains and rest progressively altered the stimulation response. Finally, after just 2 min (∼10%) of repetitive stimulation, we were able to predict poststimulation connectivity changes with high discriminability. Together, this work reveals a relationship between stimulation dynamics and poststimulation connectivity changes in humans. Thus, measuring neural activity during stimulation can inform future plasticity-inducing protocols. [ABSTRACT FROM AUTHOR]

Recent applications of simultaneous scalp electroencephalography (EEG) and transcranial magnetic stimulation (TMS) suggest that adapting stimulation to underlying brain states may enhance neuroplastic effects of TMS. It is often assumed that longer-lasting effects of TMS on brain function may be mediated by phasic interactions between TMS pulses and endogenous cortical oscillatory dynamics. The mechanisms by which TMS exerts its neuromodulatory effects, however, remain unknown. Here, we discuss evidence concerning the functional effects on synaptic plasticity of oscillatory cross-frequency coupling in cortical networks as a potential framework for understanding the neuromodulatory effects of TMS. We first discuss evidence for interactions between endogenous oscillatory brain dynamics and externally induced electromagnetic field activity. Alpha band (8–12 Hz) activities are of special interest here because of the wide application and therapeutic effectiveness of rhythmic TMS (rTMS) using a stimulus repetition frequency at or near 10 Hz. We discuss the large body of literature on alpha oscillations suggesting that alpha oscillatory cycles produce periodic inhibition or excitation of neuronal processing through phase-amplitude coupling (PAC) of low-frequency oscillations with high-frequency broadband (or gamma) bursting. Such alpha-gamma coupling may reflect excitability of neuronal ensembles underlying neuroplasticity effects of TMS. We propose that TMS delivery with simultaneous EEG recording and near real-time estimation of source-resolved alpha-gamma PAC might be used to select the precise timing of TMS pulse deliveries so as to enhance the neuroplastic effects of TMS therapies. [ABSTRACT FROM AUTHOR]

Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell–based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions. [ABSTRACT FROM AUTHOR]

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