Search

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC. Editor's summary: Tumor-associated macrophages (TAMs) promote tumor growth and immune suppression, but how TAMs develop from circulating monocytes and local tissue-resident macrophages remains incompletely understood. Using a model of pancreatic ductal adenocarcinoma (PDAC) in monocyte fate-mapping mice, Dunsmore et al. examined the dynamics of the monocyte-to-macrophage transition in tumors. A population of "intermediate" TAMs gave rise to two more differentiated TAM subsets, distinguishable by their distinct surface marker phenotype, dependence on the transcription factor Maf, migratory behavior, and localization in tumors. These findings provide a time- and space-resolved picture of TAM heterogeneity and development in PDAC, which could guide the future development of TAM-targeted therapeutic strategies. —Claire Olingy [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1β+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2–IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.Single-cell and spatial gene expression analyses of pancreatic ductal adenocarcinoma uncover a population of interleukin-1β-expressing macrophages that drive inflammatory reprogramming of neighboring tumour cells leading to disease progression and poor prognosis for patients. [ABSTRACT FROM AUTHOR]

Pediatric anxiety disorders and sleep-related problems (SRPs) are highly prevalent and are associated with serious health or psychopathological consequences. This narrative review aims to provide an overview of the current evidence of the associations between anxiety disorders and SRPs, to examine how this relationship may affect treatment, and to evaluate future directions for the field. Despite their strong bi-directional relationship, SRPs are often neglected in pediatric anxiety literature. There is little consensus on the conceptualization and related measurements of SRPs, which has led to methodological limitations and difficulties. Furthermore, available research suggests that anxiety treatment alone may be inadequate as clinically impairing SRPs were still present post-treatment, which may, in turn, diminish effects of therapy. Understanding the implications of the relationship between anxiety and SRPs on treatment outcomes may be helpful in recognizing opportunities for high impact and enduring interventions. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic led to increased neurology and palliative care needs. We compare the characteristics of COVID-19 positive vs negative patients who received consultation by neurology and palliative care services during the 2020 COVID-19 surge in New York City to see how the groups differ in their consultation needs and to identify opportunities to improve care. Methods: This retrospective analysis was performed within a multi-center hospital system in New York City, USA over a 2-month period (15 March to 15 May, 2020) which represented the peak of the first COVID-19 wave. Hospitalized patients who received a consultation from neurology and palliative care services were included. The patients were classified according to COVID-19 status (positive or negative based on PCR testing). Data abstracted from chart review included demographic data, details of neurology and palliative care consultations, duration of admission, ICU admission, intubation, code status, and death. Results: The study included 70 patients who tested positive for COVID-19 and 39 patients who tested negative for a total of 109 patients. Compared to the patients who tested negative for COVID-19, the patients who tested positive for COVID-19 were more likely to have palliative care consultation for management of goals of care (70 [100%] vs 33 [84.6%], P =.003) and less likely for management of symptoms (2 [2.9%] vs 7 [17.9%], P =.02). Conclusion: The findings emphasize the need for collaboration between palliative care and neurology, which was heightened during the COVID-19 pandemic. There was a particular need for communication surrounding goals of care. [ABSTRACT FROM AUTHOR]

Simple Summary: Hematological indices such as neutrophil-lymphocyte ratio (NLR) have been found to be prognostic for survival outcomes, with higher NLR portending a worse prognosis in primary central nervous system lymphomas (PCNSLs) and other cancers. However, corticosteroids, commonly used for reducing cerebral edema, as well as being a part of systemic treatment, subsequently alter the balance of neutrophil and lymphocyte composition in the peripheral circulation. We hypothesized that the response to corticosteroids may correlate with the response of PCNSL to systemic treatment and survival. We, therefore, investigated the NLR before and after steroids, and found that higher post-steroid NLR was paradoxically correlated with better survival. We thus developed a new decision-tree-based prognostic score using age, post-steroid NLR and pre-steroid NLR, and showed that it stratified patients into three risk profiles that predicted overall survival with good discrimination and calibration in patient cohorts across two different centers. Background: Ratios of differential blood counts (hematological indices, HIs) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSLs), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HIs could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). Methods: This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HIs were calculated at three time-points: baseline (pre steroid), pre chemoimmunotherapy (post steroid) and post chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan–Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan–Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. Results: A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR ≥ 4.0, HR 0.42, 95% CI: 0.21–0.83, p = 0.01) only. For platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), OS was better for lower post-chemoimmunotherapy PLR (dichotomized at PLR ≥ 241, HR 2.27, 95% CI: 1.00 to 5.18, p = 0.05) and lower pre-chemoimmunotherapy (post-steroid) LMR (dichotomized at LMR ≥25.7, HR 2.17, 95% CI: 1.10 to 4.31, p = 0.03), respectively, only. The decision-tree model using age ≤70, post-steroid NLR >4.0, and pre-steroid (baseline) NLR <2.5 and the division of patients into three risk profiles—low, medium, and high—achieved good accuracy (area-under-curve of 0.78), with good calibration (Brier score: 0.16) for predicting 2-year overall survival. Conclusion: We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed for accurate and well-calibrated stratification into three risk groups. [ABSTRACT FROM AUTHOR]

There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition, origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Lactating women can produce protective antibodies in their milk after vaccination, which has informed antenatal vaccination programs for diseases such as influenza and pertussis. However, whether SARS-CoV-2-specific antibodies are produced in human milk as a result of COVID-19 vaccination is still unclear. In this study, we show that lactating mothers who received the BNT162b2 vaccine secreted SARS-CoV-2-specific IgA and IgG antibodies into milk, with the most significant increase at 3–7 days post-dose 2. Virus-specific IgG titers were stable out to 4–6 weeks after dose 2. In contrast, SARS-CoV-2-specific IgA levels showed substantial decay. Vaccine mRNA was detected in few milk samples (maximum of 2 ng/ml), indicative of minimal transfer. Additionally, infants who consumed post-vaccination human milk had no reported adverse effects up to 28 days post-ingestion. Our results define the safety and efficacy profiles of the vaccine in this demographic and provide initial evidence for protective immunity conferred by milk-borne SARS-CoV-2-specific antibodies. Taken together, our study supports recommendations for uninterrupted breastfeeding subsequent to mRNA vaccination against COVID-19. [ABSTRACT FROM AUTHOR]

Background and Purpose: While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently, we have reported that the dipyrone metabolite 4‐aminoantipyrine (4‐AA) reduces PGE2‐induced pain‐related behaviour through cannabinoid CB1 receptors. Here, we ascertained, in naive and PGE2‐induced "inflamed" conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4‐AA‐induced analgesic effects. Experimental Approach The effect of local administration of 4‐AA (160 μg per paw) on capsaicin (0.12 μg per paw) injection‐induced pain‐related behaviour and 4‐AA's effect on 500‐nM capsaicin‐induced changes in intracellular calcium concentration ([Ca2+]i) in cultured primary sensory neurons were assessed in vivo and in vitro, respectively. Key Results: 4‐AA reduced capsaicin‐induced nociceptive behaviour in naive and inflamed conditions through CB1 receptors. 4‐AA (100 μM) reduced capsaicin‐induced increase in [Ca2+]i in a CB1 receptor‐dependent manner, when PGE2 was not present. Following PGE2 application, 4‐AA (1–50 μM) increased the [Ca2+]i. Although 4‐AA activated both TRPV1 and TRPA1 channels, increased [Ca2+]i was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB1 receptors reduced both the excitatory and desensitising effects of 4‐AA. Conclusion and Implications: CB1 receptor‐mediated inhibition of TRPV1 channels and TRPV1‐mediated Ca2+‐influx‐ and CB1 receptor‐dependent desensitisation of TRPV1 channels contribute to the anti‐nociceptive effect of 4‐AA in naive and inflamed conditions respectively. Agonists active at both CB1 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions. [ABSTRACT FROM AUTHOR]

T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4+ naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4+ T cells preferentially differentiate into FOXP3+ regulatory T (Treg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for Treg differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed Treg cells that are inactive in adult naïve T cells and show that fetal-derived induced Treg (iTreg) cells retain this transcriptional program. We show that a subset of Treg-specific enhancers is accessible in fetal naïve T cells, including two active superenhancers at Helios. Helios is expressed in fetal naïve T cells but not in adult naïve T cells, and fetal iTreg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iTreg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iTreg cells such as IL10, and increased expression of proinflammatory genes including IFNG. Consequently, Helios knockout fetal iTreg cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal Treg differentiation and fine-tuning eventual Treg function. The Treg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iTreg populations for adoptive cellular therapies. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens. [ABSTRACT FROM AUTHOR]

Sentinel lymph node biopsy (SLNB) is a minimally invasive lymphatic mapping technique, used to identify lymph node micrometastases and stage multiple cancer types. Despite the performance of SLNB for thyroid cancer having been under study since 1998, its role has remained controversial. The objective of this review is to summarize current research reporting on SLNB for thyroid cancer, focusing on recent studies of its application to differentiated thyroid cancer. The technique and potential benefits of SLNB are reviewed with regards to its ability to identify lymph node metastases, aid in cancer prognostication, and direct surgical and medical treatment. [ABSTRACT FROM AUTHOR]

Fibro-osseous pseudotumour of the digit (FOPT) is a rare, benign lesion of proliferating spindled myofibroblasts found in the soft tissue of the distal aspect of the digits. Misdiagnosis as malignant neoplasms such as osteosarcomas results in needlessly aggressive surgery and hinders reconstruction. We report the case of a 6-year-old girl presenting with an enlarging lesion of the left hallux for over a year, causing elevation of the medial nail fold of the left big toe over the distal phalanx. An incisional biopsy was undertaken revealing a lesion histopathologically consistent with a diagnosis of fibro-osseous pseudotumour. Accurate diagnosis through clinical reasoning and histopathology prevented digit amputation. Level of evidence: Level V, diagnostic study [ABSTRACT FROM AUTHOR]

SARS-CoV-2-specific antibody responses are engendered in human milk after BNT162b2 vaccination. However, the emergence of variants of concern (VOCs) raises concerns about the specificity of and potential cross-protection mediated by milk antibody responses, which are crucial for passive immunity transferred from breastfeeding mothers to their infants. In this study, we collected milk samples at three different time points pre- and post-vaccination, and measured milk IgA antibody binding to the receptor binding domain (RBD) of the original Wuhan-Hu-1 strain, and the four VOCs, namely Alpha, Beta, Gamma and Delta. We report a significant level of anti-RBD IgA in milk collected at 4–6 weeks after the second dose of vaccination compared to pre-vaccination. We observed around a 30% reduction in binding to most VOCs, including the major circulating Delta variant, compared to the original Wuhan-Hu-1 strain. As COVID-19 vaccines may take some time to be approved for infants, these individuals remain at risk for severe disease and rely mainly on transferred passive immunity. Our findings support the current recommendations for vaccinating lactating women with the aim of transferring mucosal immunity to breastfeeding infants. [ABSTRACT FROM AUTHOR]

Background. The role of vitamin D in the body's ability to fight influenza and URI's may be dependent on regulation of specific cytokines that participate in the host inflammatory response. The aim of this study was to test the hypothesis that vitamin D can influence intracellular signaling to regulate the production of cytokines. Subjects and Methods. This study was a 3-month prospective placebo-controlled trial of vitamin D3 supplementation in ambulatory adults [Li-Ng et al., 2009]. 162 volunteers were randomized to receive either 50 μg/d (2000 IU) of vitamin D3 or matching placebo. 25(OH)D and the levels of 10 different cytokines (IL-2, 4, 5, 6, 8, 10, 13, GM-CSF, IFN-γ, TNF-α) weremeasured in the serum of participants at baseline and the final visit. There were 6 drop-outs from the active vitamin D group and 8 from the placebo group. Results. In the active vitamin D group, we found a significant median percent decline in levels of GM-CSF (-62.9%, P < .0001), IFN-γ (-38.9%, P < .0001), IL-4 (-50.8%, P = .001), IL-8 (-48.4%, P < .0001), and IL-10 (-70.4%, P < .0001). In the placebo group, there were significant declines for GM-CSF (-53.2%, P = .0007) and IFN-γ (-34.4%, P = .0011). For each cytokine, there was no significant difference in the rate of decline between the two groups. 25(OH)D levels increased in the active vitamin D group from a mean of 64.3 ± 25.4 nmol/L to 88.5 ± 23.2 nmol/L. Conclusions. The present study did not show that vitamin D3 supplementation changed circulating cytokine levels among healthy adults. [ABSTRACT FROM AUTHOR]

Introduction: The available treatment options for euvolemic and hypervolemic hyponatremia are limited, and consist mainly of fluid restriction, diuresis, or hypertonic solutions. Most of these therapies are neither well tolerated nor totally effective, and many are associated with significant adverse effects. Vasopressin receptor antagonists, also known as vaptans, are a new class of agents that now offer an additional treatment option for hyponatremic patients. Conivaptan hydrochloride, a competitive antagonist of vasopressin V1a and V2 receptors, is the first agent in this class to be approved for treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Aims: This review critically assesses the evidence that support the use of conivaptan for the treatment of patients with euvolemic and hypervolemic hyponatremia. Evidence review conclusion: Conivaptan is effective in raising serum sodium levels in a predictable and safe fashion in euvolemic and hypervolemic hyponatremic patients. Conivaptan provides the first molecularly targeted approach for correcting hyponatremia in hospitalized patients. [ABSTRACT FROM AUTHOR]