-
Saudi Medical Journal Jul 2024To ascertain the prevalence of transfusion transmissible infections (TTIs) across diverse donor groups in the Najran province. Additionally, to establish a potential...
OBJECTIVES
To ascertain the prevalence of transfusion transmissible infections (TTIs) across diverse donor groups in the Najran province. Additionally, to establish a potential association between the development of TTI and the donors' blood group, as determined by the ABO/Rh blood grouping system.
METHODS
Blood donation data of 4120 donors, spanning from January to December 2020, were retrospectively reviewed. The blood were screened for TTI markers, including hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc), anti-hepatitis C virus (anti-HCV), anti-human immunodeficiency viruses 1 and 2 (anti-HIV1&2), anti-human T-lymphotropic virus types 1 and 2 (anti-HTLV-1&2), and syphilis antigen.
RESULTS
Positive TTI markers were detected in 10.9% of the donors. The most detected TTI marker was anti-HBc (8.9%), followed by HBsAg (0.7%). Other markers were individually detected in <1% of the donors. Anti-HBc-positive was significantly elevated among non-Saudi blood donors. There was an association between age groups and anti-HCV (=0.002), anti-HTLV (=0.004) and syphilis antigen (=0.02) markers positivity. The AB positive blood group exhibited the most positivity for TTI markers, followed by O positive blood group. Similarly, association was found between ABO group and HBsAg (=0.01), anti-HBc (=0.001), and anti-HCV (<0.001) markers positivity.
CONCLUSION
Emphasis on implementing robust screening measures for donated blood is underscored by this study. There is the need for future study to extensively evaluate TTI status to enhance our understanding of the trend in TTI.
Topics: Humans; ABO Blood-Group System; Adult; Hepatitis B Surface Antigens; Saudi Arabia; Male; Blood Donors; Retrospective Studies; Female; Middle Aged; Biomarkers; Syphilis; Young Adult; Transfusion Reaction; Prevalence; Adolescent; Hepatitis B; Hepatitis B Antibodies; HIV Infections
PubMed: 38955448
DOI: 10.15537/smj.2024.45.7.20240338 -
Learning & Memory (Cold Spring Harbor,... Jun 2024Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not...
Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not clear. Here, we used longitudinal in vivo Ca imaging in the barrel cortex of awake mice to test the hypothesis that increased excitatory synaptic strength during the learning of a whisker-dependent sensory-association task would be correlated with enhanced stimulus-evoked firing. To isolate stimulus-evoked responses from dynamic, task-related activity, imaging was performed outside of the training context. Although prior studies indicate that multiwhisker stimuli drive robust subthreshold activity, we observed sparse activation of L2/3 pyramidal (Pyr) neurons in both control and trained mice. Despite evidence for excitatory synaptic strengthening at thalamocortical and intracortical synapses in this brain area at the onset of learning-indeed, under our imaging conditions thalamocortical axons were robustly activated-we observed that L2/3 Pyr neurons in somatosensory (barrel) cortex displayed only modest increases in stimulus-evoked activity that were concentrated at the onset of training. Activity renormalized over longer training periods. In contrast, when stimuli and rewards were uncoupled in a pseudotraining paradigm, stimulus-evoked activity in L2/3 Pyr neurons was significantly suppressed. These findings indicate that sensory-association training but not sensory stimulation without coupled rewards may briefly enhance sensory-evoked activity, a phenomenon that might help link sensory input to behavioral outcomes at the onset of learning.
Topics: Animals; Vibrissae; Neocortex; Mice; Somatosensory Cortex; Male; Pyramidal Cells; Mice, Inbred C57BL; Female; Association Learning
PubMed: 38955432
DOI: 10.1101/lm.053870.123 -
Journal of Oral and Maxillofacial... Jul 2024
Topics: Humans; Bisphosphonate-Associated Osteonecrosis of the Jaw; Artificial Intelligence; Information Dissemination
PubMed: 38955427
DOI: 10.1016/j.joms.2024.03.032 -
Journal For Immunotherapy of Cancer Jul 2024Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient...
BACKGROUND
Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved.
METHODS
We performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials.
RESULTS
Melanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended on required for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A KIR and partially to the NKG2A KIR NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A KIR, but not the NKG2A KIR NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins.
CONCLUSION
Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.
Topics: Humans; Killer Cells, Natural; Interferon-gamma; Melanoma; Cell Line, Tumor; Coculture Techniques
PubMed: 38955423
DOI: 10.1136/jitc-2024-009410 -
Journal For Immunotherapy of Cancer Jul 2024Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration...
BACKGROUND
Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration show reduced potential for CPI therapy. Cancer vaccines may overcome the inadequacy of existing T cells by inducing the needed antitumor T cell response to synergize with CPIs and overcome resistance.
METHODS
CT26 and TC1 tumor cells were injected subcutaneously into mice. Mice were treated with combinations of CPIs alone or a cancer vaccine specific to the tumor antigen E7 present in TC1 cells. CPIs for the TC1 model were selected because of immunophenotyping TC1 tumors. Antitumor and protumor immunity, tumor size and survival, sequence and timing of vaccine and CPI administration, and efficacy of treatment in young and aged mice were probed.
RESULTS
While "hot" CT26 tumors are treatable with combinations of second-generation CPIs alone or with anti-TGFβ, "cold" TC1 tumor reduction requires the synergy of a tumor-antigen-specific vaccine in combination with two CPIs, anti-TIGIT and anti-PD-L1, predicted by tumor microenvironment (TME) characterization. The synergistic triple combination delays tumor growth better than any pairwise combination and improves survival in a CD8+T cell-dependent manner. Depletion of CD4+T cells improved the treatment response, and depleting regulatory T cells (Treg) revealed Tregs to be inhibiting the response as also predicted from TME analysis. We found the sequence of CPI and vaccine administration dictates the success of the treatment, and the triple combination administered concurrently induces the highest E7-specific T cell response. Contrary to young mice, in aged mice, the cancer vaccine alone is ineffective, requiring the CPIs to delay tumor growth.
CONCLUSIONS
These findings show how pre-existing or vaccine-mediated de novo T cell responses can both be amplified by and facilitate synergistic CPIs and Treg depletion that together lead to greater survival, and how analysis of the TME can help rationally design combination therapies and precision medicine to enhance clinical response to CPI and cancer vaccine therapy.
Topics: Animals; Cancer Vaccines; Mice; Immune Checkpoint Inhibitors; Tumor Microenvironment; T-Lymphocytes, Regulatory; Female; Cell Line, Tumor; Humans
PubMed: 38955422
DOI: 10.1136/jitc-2024-008970 -
Journal For Immunotherapy of Cancer Jul 2024Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood...
BACKGROUND
Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.
METHODS
We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.
RESULTS
Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.
CONCLUSION
Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Topics: Animals; Mice; Antigens, CD19; Interleukin-15; Immunotherapy, Adoptive; Humans; Disease Models, Animal; Cell Line, Tumor; Female; Interleukin-15 Receptor alpha Subunit; Receptors, Chimeric Antigen; Lymphoma; Mice, Inbred BALB C; T-Lymphocytes
PubMed: 38955421
DOI: 10.1136/jitc-2023-008572 -
Journal For Immunotherapy of Cancer Jul 2024Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and...
BACKGROUND
Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking.
METHODS
We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.
RESULTS
Overall, NRs exhibited drastically lower CD8, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).
CONCLUSIONS
These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Endometrial Neoplasms; DNA Mismatch Repair; Tumor Microenvironment; Middle Aged; Aged
PubMed: 38955419
DOI: 10.1136/jitc-2024-009143 -
CMAJ : Canadian Medical Association... Jul 2024Transgender and nonbinary (TNB) people experience obstacles that create barriers to accessing health care, including stigmatization and health inequities. Our intention...
BACKGROUND
Transgender and nonbinary (TNB) people experience obstacles that create barriers to accessing health care, including stigmatization and health inequities. Our intention was to describe the lived experiences of TNB patients and identify potential gaps in the education of health care professionals.
METHODS
We conducted a qualitative descriptive study influenced by phenomenology by interviewing with TNB adults who underwent surgery in Canada within the previous 5 years. We recruited participants using purposeful and snowball sampling via online social networking sites. Audio recordings were transcribed. Two authors coded the transcripts and derived the themes.
RESULTS
We interviewed 21 participants, with a median interview duration of 49 minutes. Participants described positive and negative health care encounters that led to stress, confusion, and feelings of vulnerability. Major themes included having to justify their need for health care in the face of structural discrimination; fear and previous traumatic experiences; community as a source of support and information; and the impact of interactions with health care professionals.
INTERPRETATION
Participants detailed barriers to accessing care, struggled to participate in shared decision-making, and desired trauma-informed care principles; they described strength in community and positive interactions with health care professionals, although barriers to accessing gender-affirming care often overshadowed other aspects of the perioperative experience. Additional research, increased education for health care professionals, and policy changes are necessary to improve access to competent care for TNB people.
Topics: Humans; Female; Male; Qualitative Research; Adult; Transgender Persons; Canada; Middle Aged; Health Services Accessibility; Aged; Social Stigma; Young Adult
PubMed: 38955410
DOI: 10.1503/cmaj.240061 -
Gut Jul 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear.
DESIGN
We performed studies with ; (KC) mice or LSL-Kras; ; (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice.
RESULTS
The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1β and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation.
CONCLUSION
Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability.
PubMed: 38955401
DOI: 10.1136/gutjnl-2024-332225 -
Open Heart Jul 2024The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once...
BACKGROUND
The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.
METHODS
Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.
RESULTS
Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.
CONCLUSION
Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
Topics: Humans; Atrial Fibrillation; Factor Xa Inhibitors; Patient Selection; Stroke; Pyrazoles; Pyridones; Rivaroxaban; Male; Female; Aged; Treatment Outcome; Registries; Administration, Oral; Risk Factors; Randomized Controlled Trials as Topic; Risk Assessment; Anticoagulants; Vitamin K
PubMed: 38955399
DOI: 10.1136/openhrt-2024-002708