Cigarette Smoking as a Risk Factor for Tuberculosis in Adults: Epidemiology and Aspects of Disease Pathogenesis.

It has been noted by the World Health Organisation that cases of tuberculosis in 2022 globally numbered 10.6 million, resulting in 1.3 million deaths, such that TB is one of the infectious diseases causing the greatest morbidity and mortality worldwide. Since as early as 1918, there has been an ongoing debate as to the relationship between cigarette smoking and TB. However, numerous epidemiological studies, as well as meta-analyses, have indicated that both active and passive smoking are independent risk factors for TB infection, development of reactivation TB, progression of primary TB, increased severity of cavitary disease, and death from TB, among several other considerations. With this considerable body of evidence confirming the association between smoking and TB, it is not surprising that TB control programmes represent a key potential preventative intervention. In addition to coverage of the epidemiology of TB and its compelling causative link with smoking, the current review is also focused on evidence derived from clinical- and laboratory-based studies of disease pathogenesis, most prominently the protective anti-mycobacterial mechanisms of the alveolar macrophage, the primary intracellular refuge of M. tuberculosis. This section of the review is followed by an overview of the major strategies utilised by the pathogen to subvert these antimicrobial mechanisms in the airway, which are intensified by the suppressive effects of smoke inhalation on alveolar macrophage function. Finally, consideration is given to a somewhat under-explored, pro-infective activity of cigarette smoking, namely augmentation of antibiotic resistance due to direct effects of smoke per se on the pathogen. These include biofilm formation, induction of cellular efflux pumps, which eliminate both smoke-derived toxicants and antibiotics, as well as gene modifications that underpin antibiotic resistance.

Transforming growth factor-ß1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in patients with basal cell carcinoma.

The current study compared the levels and possible associations between systemic soluble immune checkpoints (sICPs, n = 17) and a group of humoral modulators of immune suppressor cells (n = 7) in a cohort of patients with basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). The seven humoral modulators of immunosuppressor cells were represented by the enzymes, arginase 1 and fibroblast activation protein (FAP), the chemokine, RANTES (CCL5) and the cytokines, interleukin-10 and transforming growth factor-ß1 (TGF-ß1), as well as the M2-type macrophage markers, soluble CD163 (sCD163) and sCD206. The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients (p<0.001-p<0.00001), while that of sBTLA was significantly decreased (p<0.006). Of the co-stimulatory sICPs, sCD27 and sGITR were significantly increased (p<0.0002 and p<0.0538) in the cohort of BCC patients, while the others were essentially comparable with those of the control participants; of the dual active sICPs, sHVEM was significantly elevated (p<0.00001) and TLR2 comparable with the control group. A correlation heat map revealed selective, strong associations of TGF-ß1 with seven co-stimulatory (z = 0.618468-0.768131) and four co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-ß1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells. Notably, these abnormalities were present in patients with either newly diagnosed or recurrent disease.

Filgrastim biosimilar (EP2006): A review of 15 years' post-approval evidence.

Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.

A prospective, real-world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN: a MASCC Neutropenia, Infection, and Myelosuppression Study Group initiative.

PURPOSE: Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10-20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice. METHODS: This prospective, real-world, observational, multinational, multicenter study (December 2016-October 2019) recruited patients with solid tumors or Hodgkin's/non-Hodgkin's lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration). RESULTS: In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2-3, and 1% in cycles 4-6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia. CONCLUSIONS: Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician's judgement.

Comparison of platelet-and endothelial-associated biomarkers of disease activity in people hospitalized with Covid-19 with and without HIV co-infection.

Introduction: SARS-CoV-2 elicits a hyper-inflammatory response that contributes to increased morbidity and mortality in patients with COVID-19. In the case of HIV infection, despite effective anti-retroviral therapy, people living with HIV (PLWH) experience chronic systemic immune activation, which renders them particularly vulnerable to the life-threatening pulmonary, cardiovascular and other complications of SARS-CoV-2 co-infection. The focus of the study was a comparison of the concentrations of systemic indicators o\f innate immune dysfunction in SARS-CoV-2-PCR-positive patients (n=174) admitted with COVID-19, 37 of whom were co-infected with HIV. Methods: Participants were recruited from May 2020 to November 2021. Biomarkers included platelet-associated cytokines, chemokines, and growth factors (IL-1ß, IL-6, IL-8, MIP-1α, RANTES, PDGF-BB, TGF-ß1 and TNF-α) and endothelial associated markers (IL-1ß, IL-1Ra, ICAM-1 and VEGF). Results: PLWH were significantly younger (p=0.002) and more likely to be female (p=0.001); median CD4+ T-cell count was 256 (IQR 115 -388) cells/µL and the median HIV viral load (VL) was 20 (IQR 20 -12,980) copies/mL. Fractional inspired oxygen (FiO2) was high in both groups, but higher in patients without HIV infection (p=0.0165), reflecting a greater need for oxygen supplementation. With the exception of PDGF-BB, the levels of all the biomarkers of innate immune activation were increased in SARS-CoV-2/HIV-co-infected and SARS-CoV-2/HIV-uninfected sub-groups relative to those of a control group of healthy participants. The magnitudes of the increases in the levels of these biomarkers were comparable between the SARS-CoV-2 -infected sub-groups, the one exception being RANTES, which was significantly higher in the sub-group without HIV. After adjusting for age, sex, and diabetes in the multivariable model, only the association between HIV status and VEGF was statistically significant (p=0.034). VEGF was significantly higher in PLWH with a CD4+ T-cell count >200 cells/µL (p=0.040) and those with a suppressed VL (p=0.0077). Discussion: These findings suggest that HIV co-infection is not associated with increased intensity of the systemic innate inflammatory response during SARS-CoV-2 co-infection, which may underpin the equivalent durations of hospital stay, outcome and mortality rates in the SARS-CoV-2/HIV-infected and -uninfected sub-groups investigated in the current study. The apparent association of increased levels of plasma VEGF with SARS-CoV-2/HIV co-infection does, however, merit further investigation.

Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8+ T cells, the genetic underpinnings of which remain incompletely understood. Here we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+and CD8+ T cell malignancies.

Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer.

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.

Comparison of the effects of electronic cigarette vapours and tobacco smoke extracts on human neutrophils in vitro.

Background: Electronic cigarettes (ECs) are electronic aerosol delivery systems composed of nicotine and various chemicals, which are widely used to facilitate smoking cessation. Although ECs are considered safer than cigarettes, they do, however, contain chemical toxicants, some of which may interact with cells of the host's innate immune system of which neutrophils constitute a key component. Methods: The current study was designed to compare the effects of aqueous EC aerosol extracts (ECEs; with or without nicotine) with those of cigarette smoke extract (CSE) on neutrophil and platelet reactivity in vitro. Neutrophil reactivity is characterised by the generation of reactive oxygen species (ROS), degranulation (elastase release) and the release of extracellular DNA (neutrophil extracellular trap (NET) formation: NETosis), which were measured using chemiluminescence, spectrophotometric and microscopic procedures, respectively. Platelet reactivity was measured according to the magnitude of upregulated expression of the adhesion molecule CD62P on activated cells using a flow cytometric procedure. Results: Exposure of neutrophils to either ECEs or CSE caused a significant inhibition of ROS generation and elastase release by N-formyl-l-methionyl-l-leucyl-l-phenylalanine (1 µM)-activated neutrophils. Pre-treatment of neutrophils with CSE also resulted in a marked attenuation of phorbol 12-myristate 13-acetate (6.25 nM)-mediated release of extracellular DNA, which was unaffected by the ECEs. Similarly, CSE, but not the ECEs, inhibited the expression of CD62P by platelets activated with ADP (100 µM). Conclusions: These observations suggest that ECE aerosols may inhibit some of the immuno-protective activities of neutrophils such as ROS production and elastase release by activated cells, the effect of which was not enhanced by inclusion of nicotine. The inhibitory effects of CSE were significantly more pronounced than those of ECEs, especially so for suppression of NET formation and platelet activation. If operative in vivo, these harmful immunosuppressive effects of ECEs may compromise intrinsic pulmonary antimicrobial defence mechanisms, albeit less so than cigarette smoke.

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3.

Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC.

Fixation Methods for Replacement Screws in Scaphoid Fractures: A Biomechanical Study.

Purpose: To investigate the changes in biomechanical fixation of an initial and replacement headless compression screw by quantifying interfragmentary compression and shear displacement. Methods: A bone model was created with 2 blocks of rigid polyurethane foam to simulate a fracture site. A 24-mm headless compression screw was inserted into the model at a perpendicular or oblique angle, removed, and replaced with the 22-mm screw. The 22-mm screw replaced the 24-mm screw in either the same or reverse direction of initial insertion. All 4 methods of initial and replacement screw fixation were trialed 15 times for a total of 60 trials. Two button load cells measured compression. A digital microscope recorded shear displacement. Statistical analysis was performed to determine the differences in compression and sheer between the initial and replacement screw for each angle and screw insertion group with a 2-sided paired Student t test. Results: In comparison with the average compression force achieved by placement of the primary screw, there was a significant loss of average compression force when the secondary screw was placed in the same direction and perpendicular to the fracture plane (50 N, P < .001), in the reverse direction and perpendicular to the fracture plane (9 N, P = .049), and in the same direction and 60º to the fracture plane (11 N, P < .001). A significantly greater average shear displacement was noted for initial screw insertion at oblique compared with perpendicular orientations (0.03 mm, P < .001). Conclusions: This study demonstrates loss of compression when replacing screws despite varying orientations. Additionally, shear displacement in obliquely placed screws increased compared with perpendicularly placed screws. Clinical relevance: This study provided quantitative evidence to support the importance of establishing the correct screw length initially to avoid compression loss caused by replacing a primary screw.

Dolutegravir potentiates platelet activation by a calcium-dependent, ionophore-like mechanism.

Dolutegravir is a highly potent HIV integrase strand transfer inhibitor that is recommended for first-line anti-retroviral treatment in all major treatment guidelines. A recent study has shown that people taking this class of anti-retroviral treatment have a substantially higher risk of early-onset cardiovascular disease, a condition shown previously to be associated with increased platelet reactivity. To date, few studies have explored the effects of dolutegravir on platelet activation. Accordingly, the current study was undertaken with the primary objective of investigating the effects of dolutegravir on the reactivity of human platelets in vitro. Platelet-rich plasma, isolated platelets, or buffy coat cell suspensions prepared from the blood of healthy adults were treated with dolutegravir (2.5-10 µg/ml), followed by activation with adenosine 5'-diphosphate (ADP), thrombin, or a thromboxane A2 receptor agonist U46619. Expression of platelet CD62P (P-selectin), formation of heterotypic neutrophil:platelet aggregates, and calcium (Ca2+) fluxes were measured using flow cytometry and fluorescence spectrometry, respectively. Dolutegravir caused dose-related potentiation of ADP-, thrombin- and U46619-activated expression of CD62P by platelets, as well as a significant increases in formation of neutrophil:platelet aggregates. These effects were paralleled by a spontaneous, receptor-independent elevation in cytosolic Ca2+ that appears to underpin the mechanism by which the antiretroviral agent augments the responsiveness of these cells to ADP, thrombin and U46619. The most likely mechanism of dolutegravir-mediated increases in platelet cytosolic Ca2+ relates to a combination of lipophilicity and divalent/trivalent metal-binding and/or chelating properties of the anti-retroviral agent. These properties are likely to confer ionophore-type activities on dolutegravir that would promote movement of Ca2+ across the plasma membrane, delivering the cation to the cytosol where it would augment Ca2+-dependent intracellular signaling mechanisms. These effects of dolutegravir may lead to hyper-activation of platelets which, if operative in vivo, may contribute to an increased risk for cardiometabolic co-morbidities.

Systemic Immune Dysregulation in Early Breast Cancer Is Associated With Decreased Plasma Levels of Both Soluble Co-Inhibitory and Co-Stimulatory Immune Checkpoint Molecules.

Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased. However, when analyzed according to the patients' breast cancer characteristics, these being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status and age, no significant differences were detected between the plasma levels of the various immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally, none of these biomarkers correlated with pathological complete response. This study has identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint molecules in newly diagnosed, non-metastatic breast cancer patients compared to healthy controls, which is a novel finding seemingly consistent with a state of systemic immune dysregulation. Plausible mechanisms include an association with elevated levels of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic immune quiescence/dysregulation.

Tumor-Infiltrating Lymphocytes (TILs) in Early Breast Cancer Patients: High CD3+, CD8+, and Immunoscore Are Associated with a Pathological Complete Response.

BACKGROUND: Tumor-infiltrating lymphocytes are associated with a better prognosis in early triple-negative breast cancer (TNBC). These cells can be enumerated in situ by the "Immunoscore Clinical Research" (ISCR). The original Immunoscore® is a prognostic tool that categorizes the densities of CD3+ and CD8+ cells in both the invasive margin (IM) and center of the tumor (CT) in localized colon cancer, yielding a five-tiered classification (0-4). We evaluated the prognostic potential of ISCR and pathological complete response (pCR) following neoadjuvant chemotherapy (NACT). METHODS: The cohort included 53 TNBC, 32 luminal BC, and 18 HER2-positive BC patients undergoing NACT. Pre-treatment tumor biopsies were immune-stained for CD3+ and CD8+ T-cell markers. Quantitative analysis of these cells in different tumor locations was performed using computer-assisted image analysis. RESULTS: The pCR rate was 44%. Univariate analysis showed that primary tumor size, estrogen-receptor negative, progesterone-receptor negative, luminal vs. HER2-positive vs. TNBC, high Ki-67, high densities (cells/mm2) of CD3 CT, CD8+ CT, CD3+ IM, and CD8+ IM cells were associated with a high pCR. ISCR was associated with pCR following NACT. A multivariate model consisting of ISCR and the significant variables from the univariate analysis showed a significant trend for ISCR; however, the low sample size did not provide enough power for the model to be included in this study. CONCLUSIONS: These results revealed a significant prognostic role for the spatial distributions of the CD3+, and CD8+ lymphocytes, as well as the ISCR in relation to pCR following NACT.

Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3 are markedly increased in basal cell carcinoma.

Although co-inhibitory immune checkpoint proteins are primarily involved in promoting cell-cell interactions that suppress adaptive immunity, especially tumor immunity, the soluble cell-free variants of these molecules are also detectable in the circulation of cancer patients where they retain immunosuppressive activity. Nevertheless, little is known about the systemic levels of these soluble co-inhibitory immune checkpoints in patients with various subtypes of basal cell carcinoma (BCC), which is the most invasive and treatment-resistant type of this most commonly-occurring malignancy. In the current study, we have measured the systemic concentrations of five prominent co-inhibitory immune checkpoints, namely CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3, as well as those of C-reactive protein (CRP) and vitamin D (VD), in a cohort of patients (n = 40) with BCC, relative to those of a group of control participants, using the combination of multiplex bead array, laser nephelometry and ELISA technologies, respectively. The median systemic concentrations of CRP and VD were comparable between the two groups; however, those of all five immune checkpoints were significantly elevated (P = 0.0184 - P = < 0.00001), with those of CTLA-4 and PD-1 being highly correlated (r = 0.87; P < 0.00001). This seemingly novel finding not only identifies the existence of significant systemic immunosuppression in BCC, but also underscores the therapeutic promise of immune checkpoint targeted therapy, as well as the potential of these proteins to serve as prognostic/predictive biomarkers in BCC.

Elevated Levels of Soluble CTLA-4, PD-1, PD-L1, LAG-3 and TIM-3 and Systemic Inflammatory Stress as Potential Contributors to Immune Suppression and Generalized Tumorigenesis in a Cohort of South African Xeroderma Pigmentosum Patients.

Xeroderma Pigmentosum (XP), an autosomal recessive disorder characterized by ultraviolet radiation-induced abnormalities of DNA excision and repair pathways is associated with early development of cutaneous cancers. Intracellular oxidative stress has also been proposed as a contributor to the occurrence of skin cancers. However, little is known about the possible augmentative contributions of chronic inflammation, immune suppression and oxidative stress to the pathogenesis of malignancies associated with other subtypes of XP. This has been addressed in the current study, focused on the measurement of systemic biomarkers of inflammation, immune dysfunction and oxidative damage in XP patients, consisting of XP-C, XP-D and XP-E cases, including those XP-C cases who had already developed multiple skin malignancies. The inflammatory biomarker profile measured in XP patients and healthy control subjects included the cytokines, interleukins (ILs)-2, -4, -6, -10, interferon-γ (IFN- γ) and tumor-necrosis factor-α (TNF-α), the acute phase reactant, C-reactive protein (CRP), and cotinine (as an objective indicator of smoking status). Immune suppression was detected according to the levels of five soluble inhibitory immune checkpoint proteins (CTLA-4, PD-1, PD-L1, LAG-3 and TIM-3), as well as those of vitamin D, while oxidative stress was determined according to the circulating levels of the DNA adduct, 8-hydroxy-2-deoxyguanosine (8-OH-dG). These various biomarkers were measured in plasma using immunofluorimetric, nephelometric and ELISA procedures. Significant elevations in IL-6 (P<0.01) and TNF-α (P<0.0001), but none of the other cytokines, as well as increased levels of all five soluble inhibitory immune checkpoints (P=0.032-P=0.0001) were detected in the plasma of the XP patients. C-reactive protein and vitamin D were increased and decreased, respectively (both P<0.0001), while only one participant had an elevated level of plasma cotinine. Surprisingly, the levels of 8-OH-dG were significantly (P=0.0001) lower in the group of XP patients relative to a group of healthy control subjects. The findings of increased levels of pro-inflammatory cytokines and, in particular, those of the soluble immune checkpoints, in the setting of decreased vitamin D and moderately elevated levels of CRP in XP patients suggest a possible secondary role of ongoing, inflammatory stress and immune suppression in the pathogenesis of XP-associated malignancies.

Pulmonary Toxicities Associated With the Use of Immune Checkpoint Inhibitors: An Update From the Immuno-Oncology Subgroup of the Neutropenia, Infection & Myelosuppression Study Group of the Multinational Association for Supportive Care in Cancer.

The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, with agents such as nivolumab, pembrolizumab, and cemiplimab targeting programmed cell death protein-1 (PD-1) and durvalumab, avelumab, and atezolizumab targeting PD-ligand 1 (PD-L1). Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and a variety of solid tumors, either as single agents or in combination with other anticancer modalities. Additional indications are continuing to evolve. Checkpoint inhibitors are associated with less toxicity when compared to chemotherapy. These agents enhance the antitumor immune response and produce side- effects known as immune-related adverse events (irAEs). Although the incidence of immune checkpoint inhibitor pneumonitis (ICI-Pneumonitis) is relatively low, this complication is likely to cause the delay or cessation of immunotherapy and, in severe cases, may be associated with treatment-related mortality. The primary mechanism of ICI-Pneumonitis remains unclear, but it is believed to be associated with the immune dysregulation caused by ICIs. The development of irAEs may be related to increased T cell activity against cross-antigens expressed in tumor and normal tissues. Treatment with ICIs is associated with an increased number of activated alveolar T cells and reduced activity of the anti-inflammatory Treg phenotype, leading to dysregulation of T cell activity. This review discusses the pathogenesis of alveolar pneumonitis and the incidence, diagnosis, and clinical management of pulmonary toxicity, as well as the pulmonary complications of ICIs, either as monotherapy or in combination with other anticancer modalities, such as thoracic radiotherapy.

Frontiers in Pharmacology: Review Manuscript Targeting of the Neutrophil as an Adjunctive Strategy in Non-Small Cell Lung Cancer.

Lung cancer remains the leading cause of cancer mortality in the United States, with non-small cell lung cancer (NSCLC) accounting for around 85% of cases. Of particular concern is the poor responsiveness of this malignancy to therapy, resulting in a very low 5-year survival rate (17.4%) and a prominent tendency to progress to metastatic disease. A number of very recent studies, both pre-clinical and clinical, have implicated the neutrophil in both the pathogenesis and unsatisfactory response to therapy of NSCLC. In this context, movement of neutrophils into the tumor microenvironment (TME) is a common feature of NSCLC. Indeed neutrophils are the dominant type of immune cell in the NSCLC TME, creating a highly immunosuppressive milieu that is not only conducive to tumor growth and spread, but also represents a significant obstacle to the success of anti-tumor therapy, especially novel immunotherapies. The clinically relevant adverse impact of a neutrophil predominance both systemically and in the TME of patients with NSCLC is underscored by the negative prognostic value of both a persistent neutrophilia and, in particular, a high (≥5) neutrophil:lymphocyte ratio. On a more positive note, however, recognition of the involvement of the neutrophil in both the pathophysiology of NSCLC and treatment failure has enabled identification of neutrophil-targeted strategies that have the potential to serve as adjuncts to standard anti-cancer therapies, including immunotherapy. These strategies together with a consideration of the immunosuppressive, pro-tumorigenic properties of the neutrophil represent the major thrusts of this review.

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets.

Neutrophils are important components of the innate immune system that mediate pathogen defense by multiple processes including phagocytosis, release of proteolytic enzymes, production of reactive oxygen species, and neutrophil extracellular trap formation. Abnormalities of neutrophil count and function have been described in the setting of HIV infection, with the majority of antiretroviral agents (ARVs), excluding zidovudine, having been reported to correct neutropenia. Questions still remain, however, about their impact on neutrophil function, particularly the possibility of persistent neutrophil activation, which could predispose people living with HIV to chronic inflammatory disorders, even in the presence of virally-suppressive treatment. In this context, the effects of protease inhibitors and integrase strand transfer inhibitors, in particular, on neutrophil function remain poorly understood and deserve further study. Besides mediating hemostatic functions, platelets are increasingly recognized as critical role players in the immune response against infection. In the setting of HIV, these cells have been found to harbor the virus, even in the presence of antiretroviral therapy (ART) potentially promoting viral dissemination. While HIV-infected individuals often present with thrombocytopenia, they have also been reported to have increased platelet activation, as measured by an upregulation of expression of CD62P (P-selectin), CD40 ligand, glycoprotein IV, and RANTES. Despite ART-mediated viral suppression, HIV-infected individuals reportedly have sustained platelet activation and dysfunction. This, in turn, contributes to persistent immune activation and an inflammatory vascular environment, seemingly involving neutrophil-platelet-endothelium interactions that increase the risk for development of comorbidities such as cardiovascular disease (CVD) that has become the leading cause of morbidity and mortality in HIV-infected individuals on treatment, clearly underscoring the importance of unraveling the possible etiologic roles of ARVs. In this context, abacavir and ritonavir-boosted lopinavir and darunavir have all been linked to an increased risk of CVD. This narrative review is therefore focused primarily on the role of neutrophils and platelets in HIV transmission and disease, as well as on the effect of HIV and the most common ARVs on the numbers and functions of these cells, including neutrophil-platelet-endothelial interactions.