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Background: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7 + (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation., Methods: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders., Results: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response., Conclusions: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronobiology investigations have revealed much about cellular and physiological clockworks but we are far from having a complete mechanistic understanding of the physiological and ecological implications. Here we present some unresolved questions in circadian biology research as posed by the editorial staff and guest contributors to the Journal of Circadian Rhythms. This collection of ideas is not meant to be comprehensive but does reveal the breadth of our observations on emerging trends in chronobiology and circadian biology. It is amazing what could be achieved with various expected innovations in technologies, techniques, and mathematical tools that are being developed. We fully expect strengthening mechanistic work will be linked to health care and environmental understandings of circadian function. Now that most clock genes are known, linking these to physiological, metabolic, and developmental traits requires investigations from the single molecule to the terrestrial ecological scales. Real answers are expected for these questions over the next decade. Where are the circadian clocks at a cellular level? How are clocks coupled cellularly to generate organism level outcomes? How do communities of circadian organisms rhythmically interact with each other? In what way does the natural genetic variation in populations sculpt community behaviors? How will methods development for circadian research be used in disparate academic and commercial endeavors? These and other questions make it a very exciting time to be working as a chronobiologist., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Neutrophils infiltrate several types of cancer; however, whether their presence is associated with disease progression remains controversial. Here, we show that colon tumors overexpress neutrophil chemoattractants compared to healthy tissues, leading to their recruitment to the invasive margin and the central part of colon tumors. Of note, tumor-associated neutrophils expressing tumor necrosis factor α, which usually represents an antitumoral phenotype, were predominantly located in the invasive margin. Tumor-associated neutrophils from the invasive margin displayed an antitumoral phenotype with higher ICAM-1 and CD95 expression than neutrophils from healthy adjacent tissues. A higher neutrophil/lymphocyte ratio was found at later stages compared to the early phases of colon cancer. A neutrophil/lymphocyte ratio ≤3.5 predicted tumor samples had significantly more neutrophils at the invasive margin and the central part. Moreover, tumor-associated neutrophils at the invasive margin of early-stage tumors showed higher ICAM-1 and CD95 expression. Coculture of colon cancer cell lines with primary neutrophils induced ICAM-1 and CD95 expression, confirming our in situ findings. Thus, our data demonstrate that tumor-associated neutrophils with an antitumoral phenotype characterized by high ICAM-1 and CD95 expression infiltrate the invasive margin of early-stage colon tumors, suggesting that these cells can combat the disease at its early courses. The presence of tumor-associated neutrophils with antitumoral phenotype could help predict outcomes of patients with colon cancer., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acral melanoma (AM) is the most common melanoma in non-Caucasian populations, yet it remains largely understudied. As AM lacks the UV-radiation mutational signatures that characterize other cutaneous melanomas, it is considered devoid of immunogenicity and is rarely included in clinical trials assessing novel immunotherapeutic regimes aiming to recover the antitumor function of immune cells. We studied a Mexican cohort of melanoma patients from the Mexican Institute of Social Security (IMSS) (n = 38) and found an overrepresentation of AM (73.9%). We developed a multiparametric immunofluorescence technique coupled with a machine learning image analysis to evaluate the presence of conventional type 1 dendritic cells (cDC1) and CD8 T cells in the stroma of melanoma, two of the most relevant immune cell types for antitumor responses. We observed that both cell types infiltrate AM at similar and even higher levels than other cutaneous melanomas. Both melanoma types harbored programmed cell death protein 1 (PD-1 + ) CD8 T cells and PD-1 ligand (PD-L1 + ) cDC1s. Despite this, CD8 T cells appeared to preserve their effector function and expanding capacity as they expressed interferon-γ (IFN-γ) and KI-67. The density of cDC1s and CD8 T cells significantly decreased in advanced stage III and IV melanomas, supporting these cells' capacity to control tumor progression. These data also argue that AM could respond to anti-PD-1-PD-L1 immunotherapy.

Melanoma is the deadliest form of skin cancer. It is classified as cutaneous and non-cutaneous, with the former characterized by developing in sun-exposed areas of the skin, UV-light radiation being its most important risk factor and ordinarily affecting fair skin populations. In recent years, the incidence of melanoma has been increasing in populations with darker complexion, for example, Hispanics, in which acral melanoma is highly prevalent. The WHO estimates that the incidence and mortality of melanoma will increase by more than 60% by 2040, particularly in low/medium income countries. Acral melanoma appears in the palms, soles and nails, and because of these occult locations, it is often considered different from other cutaneous melanomas even though it also originates in the skin. Acral melanoma is very rare in Caucasian populations and is often not included from genetic analysis and clinical trials. In this review, we present the worldwide epidemiology of acral melanoma; we summarize its genetic characterization and point out important signaling pathways for targeted therapy. We also discuss how genetic analyses have shown that acral melanoma carries a sufficient mutational load and neoantigen formation to be targeted by the immune system, arguing for a potential benefit with novel immunotherapeutic strategies, alone or combined with targeted therapy. This is important because chemotherapy remains the first-line treatment in non-developed nations despite a disheartening response. In summary, the increased incidence and mortality of acral melanoma in low/medium income countries calls for increasing our knowledge about its nature and therapeutic options and leveling off the asymmetric research conducted primarily on Caucasian populations., Competing Interests: Conflicts of Interest The authors declare that they do not have any conflict of interest., (Copyright © 2022 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

Melanoma is the deadliest form of skin cancer. Due to its high mutation rates, melanoma is a convenient model to study antitumor immune responses. Dendritic cells (DCs) play a key role in activating cytotoxic CD8 + T lymphocytes and directing them to kill tumor cells. Although there is evidence that DCs infiltrate melanomas, information about the profile of these cells, their activity states, and potential antitumor function remains unclear, particularly for conventional DCs type 1 (cDC1). Approaches to profiling tumor-infiltrating DCs are hindered by their diversity and the high number of signals that can affect their state of activation. Multiplexed immunofluorescence (mIF) allows the simultaneous analysis of multiple markers, but image-based analysis is time-consuming and often inconsistent among analysts. In this work, we evaluated several machine learning (ML) algorithms and established a workflow of nine-parameter image analysis that allowed us to study cDC1s in a reproducible and accessible manner. Using this workflow, we compared melanoma samples between disease-free and metastatic patients at diagnosis. We observed that cDC1s are more abundant in the tumor infiltrate of the former. Furthermore, cDC1s in disease-free patients exhibit an expression profile more congruent with an activator function: CD40 high PD-L1 low CD86 + IL-12 + . Although disease-free patients were also enriched with CD40 - PD-L1 + cDC1s, these cells were also more compatible with an activator phenotype. The opposite was true for metastatic patients at diagnosis who were enriched for cDC1s with a more tolerogenic phenotype (CD40 low PD-L1 high CD86 - IL-12 - IDO + ). ML-based workflows like the one developed here can be used to analyze complex phenotypes of other immune cells and can be brought to laboratories with standard expertise and computer capacity., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Saraí G. De León Rodríguez et al.)

Concern about the harmful effects that ultraviolet (UV) rays have on the skin of people who are routinely exposed to solar radiation has driven the industry of skin protection creams, sunglasses and clothing. Spanish Navy personnel are subject to different levels of exposure depending on their rank and function. The objective of this research is to analyze the behavioral variables associated to the effects on the skin caused by UV rays, denoted by the combined effects of perceived susceptibility and perceived severity, on their decision to purchase and wear uniforms with UV protection. A confirmatory analysis using a structural equation modeling (SEM) was performed on a sample of 100 respondents. The model results revealed a strong mediating characteristic of the intention to use, variable associated with the exogenous variables. Attitude towards the use of clothing and social influence, as well as the exogenous variable clothing action planning, on the sun protective clothing use during tactical maneuvers. These relationships were significant with p -values close to zero. However, exogenous variables related to perceived susceptibility and perceived severity in exposure to sunlight did not represent a significant influence when mediated by self-efficacy in use. The results revealed the consequence of awareness about the importance of protecting oneself and the influence that usage habits can have on the military with respect to the decision to purchase uniforms with UV protection.

Immunotherapy has improved the clinical response in melanoma patients, although a relevant percentage of patients still cannot be salvaged. The search for the immune populations that provide the best tumor control and that can be coaxed by immunotherapy strategies is a hot topic in cancer research nowadays. Tumor-infiltrating TCF-1 + progenitor exhausted CD8 + T cells seem to grant the best melanoma prognosis and also efficiently respond to anti-PD-1 immunotherapy, giving rise to a TIM-3 + terminally exhausted population with heightened effector activity. We tested Porins from Salmonella Typhi as a pathogen associated molecular pattern adjuvant of natural or model antigen in prophylactic and therapeutic immunization approaches against murine melanoma. Porins induced protection against melanomas, even upon re-challenging of tumor-free mice. Porins efficiently expanded IFN-γ-producing CD8 + T cells and induced central and effector memory in lymph nodes and tissue-resident (Trm) T cells in the skin and tumors. Porins induced TCF-1 + PD-1 + CD8 + Trm T cells in the tumor stroma and the presence of this population correlated with melanoma growth protection in mice. Porins immunization also cooperated with anti-PD-1 immunotherapy to hamper melanoma growth. Importantly, the potentially protective Trm populations induced by Porins in the murine model were also observed in melanoma patients in which their presence also correlated with disease control. Our data support the use of cancer vaccination to sculpt the tumor stroma with efficient and lasting Trm T cells with effector activities, highlighting the use of Porins as an adjuvant. Furthermore, our data place CD8 + Trm T cells with a progenitor exhausted phenotype as an important population for melanoma control, either independently or in cooperation with anti-PD-1 immunotherapy., (Copyright © 2020 León-Letelier, Castro-Medina, Badillo-Godinez, Tepale-Segura, Huanosta-Murillo, Aguilar-Flores, De León-Rodríguez, Mantilla, Fuentes-Pananá, López-Macías and Bonifaz.)

Discrepancies between clinical suspicion and pathological findings in pulmonary embolism (PE) appear to be frequent. The aim of this study was to analyze the prevalence of PE in a necropsy series of patients who have died in an acute care hospital between 1998-2017, its relationship with previous clinical suspicion, and its importance as a cause of death. It is a retrospective observational study of 350 autopsies done at the Department of Pathology. We analyzed the demographic characteristics, main clinical diagnoses stated in the autopsy request form, incidence of PE diagnosed, main autopsy findings related with the cause of death, as well as the concordance between clinical suspicion and autopsy diagnosis. In only 8% of the cases (n = 28) the clinical diagnosis of autopsy request was PE. An autopsy diagnosis of PE was done in 127 cases (36.3%); in 33 cases (25.9%) affected large pulmonary vessels; medium caliber vessels were affected in 75 cases (59.1%), and in 19 cases small vessels. The PE was considered as a contributor or cause of death in 30.9% (n = 108). However, only 15.7% of the confirmed PE cases had previous clinical suspicion. This series of necropsies shows that PE is a high prevalence finding in autopsies at an acute care hospital, and an important cause of death in a 20 years period. The finding of a low concordance with clinical diagnosis should alert the medical community on the importance of clinical suspicion in order to achieve an early diagnosis and treatment of this disease.

Since the emergence of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China at the end of 2019, when its characteristics were practically unknown, one aspect was evident: its high contagion rate. This high infection rate resulted in the spread of the virus in China, Europe, and, eventually, the rest of the world, including Mexico. At present, around 9 million people are infected, and around 470,000 have died worldwide. In this context, the need to generate protective immunity, and especially the generation of a vaccine that can protect the world population against infection in the shortest possible time, is a challenge that is being addressed in different countries using different strategies in multiple clinical trials. This opinion article will present the evidence of the induction of immune response in some of the viruses of the coronavirus family before COVID-19, such as SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus). The information collected about the induction of an immune response by SARS-CoV-2 will be presented, as well as a description of the vaccine candidates reported to date in the various ongoing clinical trials. Finally, an opinion based on the evidence presented will be issued on the potential success of developing vaccine prototypes., (Copyright: © 2020 Permanyer.)

Aphis species living on the South American native genus Mulinum are studied. Aphis vurilocensis Nieto Nafría, Brown and López Ciruelos, sp. n. is described from apterous viviparous females. Alate viviparous females, oviparous females and winged males of Aphis roberti are described. Knowledge of intraspecific variability of apterous viviparous females of A. martinezi, A. paravanoi and A. roberti is developed. An identification key of apterous viviparous females of Aphis species living on Mulinum is presented.

Kidney transplant survival has been increased with the use of cyclosporine (CyA) and antilymphocyte globulin (ALG), in spite of which both significant morbidity and mortality persist. On the other hand, immunosuppression is mostly based on the state of renal function and not on the monitoring of immunologic parameters. Therefore, it is important to apply immunological techniques for early diagnosis of over-immunosuppression and eventually to stop maintenance immunosuppression completely. Seventeen kidney transplant recipients (3 from cadavers and 14 living related) were studied. They were initially treated with either 3-5 mg/kg/d CyA, ALG and 0.5 mg/kg/d prednisolone (current treatment) or with 2 mg/kg/d azathioprine and 1 mg/kg/d prednisolone (conventional treatment). Cell-mediated lympholysis (CML) was performed between receptor and, alternatively, specific donor and third unrelated control. CML figures were higher with conventional treatment (14.73 +/- 1.69) than with current treatment (3.14 +/- 0.8) (Table 2). CML responses between receptors and third unrelated donors increased significantly with conventional therapy to 77.67 +/- 8.17, a value not different from that encountered between unrelated controls (72.7 +/- 3.9). The CML responses with the current therapy increased significantly to 34.25 +/- 2.54 but remained lower than that observed in the other group. The data suggest that the use of GAL and CyA leads to a nonspecific decrease of the immune response. It remains to determine whether or not the pattern evolves later to a donor specific hypo-response, as observed in the present study with the group with conventional treatment, confirming previous results.