Suppression Of Immune System Research Articles

Topical application of vitamin D cream in particiants with inflammatory acne due to vitamin D deficiency

Acne vulgaris (AV) represents a chronic inflammatory condition affecting pilosebaceous units, characterized by a multifactorial etiology. AV can manifest as both inflammatory and non-inflammatory skin lesions. Non-inflammatory acne is termed a comedone, which can be either closed (whiteheads) or open (blackheads). Inflammatory acne encompasses papules, pustules, nodules, and pseudocysts. The most common regions for acne occurrence are the facial region (90%), thoracic area (14%), and dorsal region (60%). In the study involving transdermal application of vitamin D cream (applied twice daily; morning and evening) in subjects with inflammatory acne due to vitamin D deficiency, 33 participants took part, comprising 8 males and 25 females. The age group most affected was 18-25 years (adolescent age), followed by a lesser impact in the 26-30 age group, and the lowest incidence observed in the late 36-45 age group. Among males, facial and thoracic regions were most affected by inflammatory acne (37.5%), while among females, the facial region showed a higher percentage of 54%, and the thoracic area was at 40%, with a minimal impact on the dorsal region (M=25%; F=8%). Reductions in inflammatory acne ranged from 100% to 10%, with substantial improvements noted in the male population, achieving 100% and 80% reduction (100% reduction: facial region 25%, thoracic area 12.5%, 80% reduction: dorsal region 25%). Similarly, the female group, with a larger sample size (25 participants), demonstrated significant reductions (100% reduction: facial region 36%, thoracic area 24%, 80% reduction: dorsal area 4%). Overall, improvements were evident in all participants, with none falling below a 30% reduction, indicating remarkable outcomes after one month of vitamin D cream use. Numerous factors contribute to the onset of inflammatory acne, with this study specifically highlighting vitamin D deficiency in the blood. Other indications include the occurrence of polycystic ovaries and reduced thyroid function in women, heightened stress, and prostate issues in men. Reduced or deficient vitamin D levels may be associated with further immune system suppression, activating the aforementioned factors. This research marks a significant stride in uncovering the manifold health benefits of vitamin D. Keywords: acne, vitamin D, participants

Abstract 3186: An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study

Abstract Background: Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, yet resistance to this therapy can lead to immune escape and disease progression. Here, we introduce WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 naturally accumulates in the spleen and remodels the splenic immune landscape in tumor-bearing mice. Pre-clinical studies have demonstrated that T cells activated by WTX-212 reduce the splenic reservoir of immunosuppressive myeloid cells, including those within tumors. This results in a systemic anti-tumor immune response and suppression of tumor growth in xenograft tumor models resistant to anti-PD-1 immunotherapies. A first-in-human (FIH) clinical trial is now investigating its potential in human cancer patients. Methods: The FIH trial (NCT05707325) is aimed to investigate the safety, pharmacokinetics, mechanisms and preliminary efficacy of WTX-212 in cancer patients with advanced malignancies. All of patients had previously received anti-PDs therapies and developed resistance to these treatments. By November 15th, 2023, 7 patients across two cohorts had received WTX-212 monotherapy (1 × 1011-2 × 1011 cells, Q3W IV). The tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. No dose-limiting toxicities or treatment-related adverse events greater than Grade 3 were reported. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control, including partial remission (PR) and stable disease (SD), was observed in 5/7 patients (DCR, 71%). One patient with esophageal cancer achieved a PR with a significant 44% reduction in target lesion size after two cycles of treatment. Two patients, one with esophageal cancer (3 lines prior therapies) and another with HPV-negative cervical cancer (4 lines prior therapies), maintained disease control for over 30 weeks after WTX-212 treatment. Consistent with preclinical findings, WTX-212 systemically induced anti-tumor responses, leading to a reduction of myeloid-derived suppressor cells (MDSCs) particularly the PMN-MDSC subset in 6/7 patients (reductions ranging from 24%-82% compared to baseline), and a median 1.5-fold increase of T cells in 7/7 patients in the peripheral blood after the 1st cycle of treatment. Conclusion: The initial promising data support further investigation and exploration of the combination therapy strategies to expand the therapeutic potential of WTX-212 in cancer patients. Erythrocyte-drug conjugation may serve as a unique strategy for targeting the peripheral immune system to treat cancers. Citation Format: Liu Yang, Xiaoqian Nie, Zheling Chen, Yuehua Liu, Jiawei Zheng, Xiaofei Gao. An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3186.

Effect of Donor Age on Endocrine Function of and Immune Response to Ovarian Grafts.

Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6-8 (D7) or 20-22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic-pituitary-ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection.

A CD38-directed, single-chain T-cell engager targets leukemia stem cells through IFN-γ–induced CD38 expression

AbstractTreatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ–induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.

Autoantigen-Dexamethasone Conjugate-Loaded Liposomes Halt Arthritis Development in Mice.

There is no curative treatment for chronic auto-inflammatory diseases including rheumatoid arthritis, and current treatments can induce off-target side effects due to systemic immune suppression. This work has previously shown that dexamethasone-pulsed tolerogenic dendritic cells loaded with the arthritis-specific antigen human proteoglycan can suppress arthritis development in a proteoglycan-induced arthritis mouse model. To circumvent ex vivo dendritic cell culture, and enhance antigen-specific effects, drug delivery vehicles, such as liposomes, provide an interesting approach. Here, this work uses anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol liposomes with enhanced loading of human proteoglycan-dexamethasone conjugates by cationic lysine tetramer addition. Antigen-pulsed tolerogenic dendritic cells induced by liposomal dexamethasone in vitro enhanced antigen-specific regulatory Tcells to a similar extent as dexamethasone-induced tolerogenic dendritic cells. In an inflammatory adoptive transfer model, mice injected with antigen-dexamethasone liposomes have significantly higher antigen-specific type 1 regulatory Tcells than mice injected with antigen only. The liposomes significantly inhibit the progression of arthritis compared to controls in preventative and therapeutic proteoglycan-induced arthritis mouse models. This coincides with systemic tolerance induction and an increase in IL10 expression in the paws of mice. In conclusion,a single administration of autoantigen and dexamethasone-loaded liposomes seems to be a promising antigen-specific treatment strategy for arthritis in mice.

CD200Rhigh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells.

Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200Rhigh neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (Treg) cells. Compared to their CD200Rlow counterparts, sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200Rhigh neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200Rhigh neutrophils expressed high levels of Igf1, which elicits the generation of Treg cells, while the administration of an α-CD200R antibody inhibited Treg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200Rhigh neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.

Exploring the Oral Manifestations and Hazards to Dental Professionals During the COVID-19 Pandemic: A Scoping Review.

The novel coronavirus (COVID-19) has inundated the whole world by causing severe acute respiratory syndrome in humans, thus posing serious public health concerns. The oral and olfactory systems are significantly impacted by the COVID-19 condition, in addition to the respiratory and digestive systems. Oral symptoms of COVID-19 can be caused by a loss in oral hygiene, immune system suppression, a decline in general health, and candidiasis due to prolonged antibiotic use. Because many aerosols and droplets are produced during various dental operations, dental professionals and dentists are at a significant risk of contracting the COVID-19 infection. Few precautionary measures include performing a pre-appointment health screening for all patients, performing aerosol-producing procedures in a designated space or operatory, using proper personal protective equipment and disinfecting the operatory between patients, and limiting the number of dental procedures at one time. Against this background, the purposes of this article are to explore the oral presentations of COVID-19 infection and to emphasize the hazards to dental professionals during COVID-19 pandemic. Additionally, few preventive measures are also highlighted.

Enhancing the Functionality of Immunoisolated Human SC-βeta Cell Clusters through Prior Resizing.

The transplantation of immunoisolated stem cell derived beta cell clusters (SC-β) has the potential to restore physiological glycemic control in patients with type I diabetes. This strategy is attractive as it uses a renewable β-cell source without the need for systemic immune suppression. SC-β cells have been shown to reverse diabetes in immune compromised mice when transplanted as ≈300µm diameter clusters into sites where they can become revascularized. However, immunoisolated SC-β clusters are not directly revascularized and rely on slower diffusion of nutrients through a membrane. It is hypothesized that smaller SC-β cell clusters (≈150µm diameter), more similar to islets, will perform better within immunoisolation devices due to enhanced mass transport. To test this, SC-β cells are resized into small clusters, encapsulated in alginate spheres, and coated with a biocompatible A10 polycation coating that resists fibrosis. After transplantation into diabetic immune competent C57BL/6 mice, the "resized" SC-β cells plus the A10 biocompatible polycation coating induced long-term euglycemia in the mice (6 months). After retrieval, the resized A10 SC-β cells exhibited the least amount of fibrosis and enhanced markers of β-cell maturation. The utilization of small SC-β cell clusters within immunoprotection devices may improve clinical translation in the future.

Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.

Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression. Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined. Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response. Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.

Microorganism-derived extracellular vesicles: emerging contributors to female reproductive health.

Extracellular vesicles (EVs) are cell-derived nanoparticles that carry small molecules, nucleic acids, and proteins long distances in the body facilitating cell-cell communication. Microorganism-derived EVs mediate communication between parent cells and host cells, with recent evidence supporting their role in biofilm formation, horizontal gene transfer, and suppression of the host immune system. As lipid-bound bacterial byproducts, EVs demonstrate improved cellular uptake and distribution in vivo compared to cell-free nucleic acids, proteins, or small molecules, allowing these biological nanoparticles to recapitulate the effects of parent cells and contribute to a range of human health outcomes. Here, we focus on how EVs derived from vaginal microorganisms contribute to gynecologic and obstetric outcomes. As the composition of the vaginal microbiome significantly impacts women's health, we discuss bacterial EVs from both healthy and dysbiotic vaginal microbiota. We also examine recent work done to evaluate the role of EVs from common vaginal bacterial, fungal, and parasitic pathogens in pathogenesis of female reproductive tract disease. We highlight evidence for the role of EVs in women's health, gaps in current knowledge, and opportunities for future work. Finally, we discuss how leveraging the innate interactions between microorganisms and mammalian cells may establish EVs as a novel therapeutic modality for gynecologic and obstetric indications.

Infestação de Argulus sp. associada a bacteriose em carpas ornamentais - relato de caso

ABSTRACT The aim of this study was to diagnose the causative agent of carp (Cyprinidae) mortality in an artificial lake used for recreation in Jaraguá do Sul, state of Santa Catarina, in February 2018. The fish showed symptoms, including skin ulceration, hemorrhages on the surface of the body, loss of scale and increased mucus production. Through the proteomic profile, using the MALDI-TOF technique, three bacterial isolates were identified as Aeromonas veronii, A. hydrophila and Citrobacter freundii. In addition, in the mucus scraping, a large number of the ectoparasite Argulus was observed. A blood collection was carried out to verify the hematological indices of the animals and a decrease in the the hematocrit value, erythrocyte count, and differential leukocyte count was observed. These findings indicate that Argulus infection increases the carp’s susceptibility to bacterial diseases and contributes to the suppression of the innate immune system and consequent increase in mortality.

Стан загального імунітету в породілей із гнійними ранами під час воєнних дій

Purpose - to study the immune status of women giving birth with an infection of an obstetric surgical wound in the conditions of war, which will make it possible to develop and implement a pathogenetically justified method of wound infection therapy in the postpartum period. Materials and methods. We studied the immune status of 66 women in labor with an infection of an obstetric surgical wound in the conditions of war from February 24, 2022 and compared it with the indicators of general immunity of 76 women in labor with an infection of an obstetric surgical wound in peacetime. The material for the study of general immunity was peripheral blood, which was taken from the moment of infection of the obstetric surgical wound. To assess the state of general immunity, the total number of T lymphocytes (CD3+), their immunoregulatory subpopulations - T helpers/inducers (CD4+) and T suppressors/killers (CD8+), the number of B lymphocytes (CD22+), NK cells (CD16+) were counted), the immunoregulatory index (CD4+/CD8+) was calculated, the concentration of circulating immune complexes and immunoglobulins of classes A, M, G, phagocytic index and phagocytic number were determined. Statistical data processing was carried out using the package of application programs Microsoft Excel 5.0 and using the standard version Statistica 8.0. The difference in indicators was considered statistically significant at Р<0.05. Results. In women in labor with purulent wounds under the conditions of war under stressful conditions, there is a greater suppression of systemic immunity than in women in labor with this pathology in peacetime, which was manifested by T lymphopenia (decrease in CD3+ by 1.4 times, decrease in the level of T cells with helper activity (CD4+) by 1.2 times, immunoregulatory index (Tx/Tc) by 1.3 times), a decrease in the number of B lymphocytes (CD22+) and NK cells (CD16+) by an average of 1.2 times, a decrease indicators of immunoglobulins of classes A, M, G by an average of 1.3 times, phagocytic index) and phagocytic number relatively by 1.3 and 1.6 times, which led to an increase in the level of circulating immune complexes by 1.1 times. The absence of a significant difference between indicators of general immunity in parturient women with purulent wounds of the perineum and anterior abdominal wall was confirmed, which confirms the established doctrine that wounds of different localizations heal according to general laws and the body, namely the immune system, reacts equally to the wound process of any localization. Conclusions. When prescribing the treatment of an infection of an obstetric surgical wound, do not take into account the localization of the wound, since wounds of different localizations heal according to general laws and the immune system reacts in the same way. In women in labor with purulent wounds in wartime conditions, under stress, there is more suppression of systemic immunity than in women in labor with an infection of an obstetric surgical wound in peacetime, which increases the development and spread of the purulent-inflammatory process, increases the risk of severe septic complications, which leads to the development and implementation of a pathogenetically justified method of therapy of obstetric surgical wound infection in wartime conditions. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

The role of nursing care in the management of post-burn epidermal cancer: A narrative review

Severe burns, affecting over 20% of the body, induce systemic dysfunction and immune suppression, correlating with increased cancer risk, especially skin cancer. Nurses play a crucial role in averting complications, which is explored in this study through a comprehensive literature review. The literature review focused on nursing care for post-burn skin cancer; a systematic search covered databases including Magiran, Scientific Information Database, and PubMed and Google Scholar search engine. Keywords "nursing", "skin cancer", and "burn" were strategically combined with Boolean operators. From an initial 580 articles, 10 met eligibility post-screening. The results have shown that optimal care for burn patients necessitates an interdisciplinary approach with the burn nurse at its core, coordinating patient care across multiple disciplines. The nurse's responsibilities encompass a comprehensive understanding of multisystem organ failure, critical care methodologies, diagnostic procedures, and psychosocial skills. Meticulous wound care, infection prevention, and pain management are pivotal, with the nurse actively engaging in nursing research. The origin of cancers within burns involves hypotheses of persistent cell proliferation, chronic inflammation, toxin exposure, and compromised immunological defense. Nursing care, particularly in detecting and treating wound inflammation, is pivotal in preventing cancer. Nurses contribute to patient education on skin cancer prevention, emphasizing lifestyle choices and providing crucial psychological support. Nursing diagnoses, based on symptomatology studies, include "risk for impaired skin integrity", "impaired skin integrity", "acute pain", "chronic pain", and "impaired comfort". These diagnoses guide tailored interventions to prevent skin cancer incidence.In sum, nurses are pivotal in comprehensive burn care, overseeing wound care, infection prevention, and patient education on UV radiation dangers. They advocate healthy lifestyles to reduce skin cancer risk, provide psychological support, and encourage commitment to prevention practices. Nursing diagnoses guide tailored interventions, contributing to ongoing improvements in burn care and enhancing the quality of life for survivors.

FROM FIELD TO FORKS: A DEEP DIVE INTO AFLATOXIN CONTAMINATION IN FOOD ITEMS

Aflatoxin contamination in food items pretences a significant hazard to global foodstuff safety, public health, and economic stability. This assessment comprehensively examines the sources, risks, and potential solutions associated with aflatoxin contamination in various food products. Aflatoxins, produced by moulds of the Aspergillus genus, contaminate crops during cultivation, harvest, storage, and processing stages. Consumption of aflatoxin-contaminated food items has been linked to severe health issues, including liver cancer, stunted growth, and immune system suppression. This review delves into the diverse sources of aflatoxin contamination, ranging from agricultural practices and environmental factors to storage conditions. The risks associated with aflatoxin exposure are explored in detail, emphasizing the global impact on both human health and economies, especially in vulnerable communities reliant on staple crops. Furthermore, the review discusses multifaceted solutions aimed at mitigating aflatoxin contamination. These solutions encompass agricultural strategies such as crop rotation, improved irrigation methods, and biocontrol agents, as well as advancements in food processing techniques like sorting, washing, and hermetic storage. Regulatory measures and international standards are critically evaluated, highlighting their role in ensuring food safety and preventing aflatoxin-related health crises. Keywords : Aflatoxin, Contamination, Public Health, Global Foodstuff Safety

Effective medium for Photorhabdus luminescens bioinsecticide production and exploration of optimal mixture with Bacillus thuringiensis subsp. aizawai against Plutella xylostella

BackgroundPlutella xylostella is a major pest of cruciferous vegetables worldwide. We evaluated a biopesticide using different culture treatments of Photorhabdus luminescens (ATCC 29,999) and Bacillus thuringiensis subsp. aizawai and examined their insecticidal activity against Pl. xylostella. MethodsL8 and L9 Taguchi orthogonal designs were adopted to evaluate the optimal culture medium for enhanced insecticidal activity. Feeding bioassays were conducted to determine the potential synergistic effects of combining B. thuringiensis and Ph. luminescens, and the most effective synergistic combination was identified by analyzing the time–mortality response against Pl. xylostella. Significant FindingsAnalysis of the pH value indicates that Ph. luminescens has enhanced tolerance to acidic conditions and can alkalize the medium. Among the various medium combinations, Ph. luminescens optimized using A3B1C3N2—d10 × concentration, 24-h cultivation time, 1.25 % molasses as the carbon source, and a nitrogen source consisting of yeast extract powder, yeast powder, and amino acids (0.2:0.3:0.5 %)—resulted in the highest insect mortality. Synergistic interactions between B. thuringiensis and Ph. luminescens were observed in the 1:1 mixture, likely due to immune system suppression. These results highlight the potential of combining Ph. luminescens and B. thuringiensis to prepare a potent bioinsecticide against Pl. xylostella and other lepidopteran pests, thereby decreasing the reliance on chemical pesticides.

The effect of smoking on open carpal tunnel release recovery

IntroductionThis study examines the relationship between smoking status and surgical outcomes in open carpal tunnel release. Smoking status has previously been correlated with orthopedic surgical complications unless smoking cessation occurs at least 4 weeks prior to surgery; however, the effect of smoking on open carpal tunnel release has not been specifically examined. MethodsThis study is a retrospective review of patient charts over the last 5 years (n = 131). Smoking status was determined at the time of carpal tunnel release from the patients’ charts. Patients were dichotomized as smokers (n = 58) or non-smokers (n = 73). Data comprised preoperative pain, postoperative pain at 2 and 6 weeks, postoperative wrist stiffness, wound healing time, and infection status. Data were compared on chi square, Fisher exact, and one-sided Fisher exact tests. ResultsInfection rates were significantly higher in smokers. Postoperative numbness and wrist stiffness were also significantly higher in smokers. Smokers reported higher postoperative pain scores at 2 and 6 weeks. Non-smokers were also significantly more likely to report complete pain resolution at 6 weeks. DiscussionIn the present study smoking was associated with surgical outcome complications in open carpal tunnel release. This could be attributed to immune system suppression or to poor wound healing, both of which are known side-effects of smoking. Pain scores 6 weeks post-surgery were significantly higher in smokers than in non-smokers. Smokers undergoing open carpal tunnel release need to understand the risk of surgical complications and should consider smoking cessation to optimize their chances of successful surgery. ConclusionPatients who were active smokers showed poorer recovery from open carpal tunnel surgery than non-smoking patients.

Casting Hope, Defying Odds: Unveiling the Impact of Haplo-Identical Stem Cell Transplant in Myeloid Malignancies - a Tertiary Cancer Care Center Experience

Background & Significance: Only 30% to 40% of patients in need of a curative stem cell transplant (SCT) could find a suitable matched sibling donor. For Indian patients, the likelihood of locating a 10/10 HLA identical unrelated donor within limited donor registries is approximately 14%. However, this probability has the potential to rise to 60% if registries with over 1,000,000 registered donors are available. 1,2 Consequently, there is an increasing inclination in India to perform haploidentical transplantations utilizing the post-transplantation cyclophosphamide (PTCY) platform developed by the Johns Hopkins group. 3 The outcomes of haploidentical stem cell transplantation (haplo-SCT) for the treatment of AML were enhanced in the 1990s with the introduction of a T-cell depletion (TCD) strategy followed by a myeloablative conditioning regimen. 4,5 In the last two decades, significant progress in haplo-SCT for hematological malignancies, especially AML, includes donor selection algorithms, improved grafts, GVHD prophylaxis, and enhanced immunologic recovery, benefiting patients. 6 Here, we present our experience of haplo-identical stem cell transplants in myeloid malignancies at our centre. Study design & Methods: We conducted a retrospective study at our site. Patients with myeloid malignancy who underwent haplo-identical stem cell transplant between Jan 2018 - Jan 2023 were included in the study and the follow-up was done till July 2023. Haplo-identical transplants done for diagnosis other than myeloid malignancy were excluded. The objectives of the study were to assess the non-relapse mortality [NRM] rate at day +100, relapse rate, graft-versus-host disease - free relapse-free survival [GRFS] and overall survival [OS] of the study cohort. GRFS was defined as a combined outcome including mortality from any cause, recurrence of malignancy, acute GVHD of grade 3 to 4, or chronic GVHD necessitating systemic immune suppression therapy. 7 Descriptive statistics (including median, mean, and range) were used to describe the central tendency and dispersion of variables. The probability of overall survival [OS] and graft versus host disease relapse free survival [GRFS] was estimated by the method of Kaplan and Meier. Probabilities of relapse or progression of malignancy, RRM, and day-100 NRM were summarized using cumulative incidence estimates All statistical analysis were done using statistical package for social science software (SPSS 21, IBM SPSS Statistics). Results: We have analysed 29 patients with various myeloid malignancies who have underwent haploidentical SCT from Jan 2018 to Jan 2023. There were 28 AML and 1 MDS patients. The median age was 35 (range, 16 - 59) and there were 22 males and 7 females. Conditioning intensity was myeloablative in 19 (65.5%), reduced intensity conditioning (RIC) in 8 (27.6%) and NMA in 2 (6.9%) patients. There were 10 (34.5%) patients in complete remission 1(CR1) and 19 (65.5%) in CR2. Hematopoietic Cell Transplantation-specific Comorbidity Index [HCT-CI] score was as low 11 (37.9%), intermediate 8 (27.6%) and high 10 (34.5%) patients respectively. Median time to neutrophil engraftment was 16 days (range, 12 - 25) and platelet engraftment was 17 days (range, 11 - 32). Median CD34 stem cell dose was 6.25 x 10*6/kg (range, 3.1 - 8.09) x 10*6/kg. Grade II-IV acute GVHD over first +100 days post SCT was observed in 6 (20.7) patients, and grade III-IV acute GVHD and chronic GVHD at follow up of one year was 3 (10.3) respectively. CMV reactivation by +100days was seen in 18 (62.06%) patients. Relapse was seen in 10 (34.5%) patients, out of which 2 patients are alive and 8 expired due to progressive disease. At median follow up of 13 months, OS is 60.3% (CI: 39.7% - 75.9%) and GRFS is at a median follow-up of 6 month was 51.2% (CI: 35.6% - 71%). Fig:1 NRM was 10.3% and 17.24% at +100 days and at last follow-up respectively. Fig:2 Conclusion: In conclusion, our study demonstrates favorable outcomes in terms of NRM (non-relapse mortality) with a low rate of 10.3% at 100 days after haploidentical SCT. The results also show promising overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates, supporting the potential of haploidentical transplants as an effective treatment option for myeloid malignancies. Further long-term follow-up and research are needed to validate and optimize these findings.

The expression changes of PD-L1 and immune response mediators are related to the severity of primary bone tumors

The expression pattern, diagnostic value, and association of PD-L1, IFN-γ and TGF-β with bone tumor type, severity, and relapse are determined in this study. 300 human samples from patients with osteosarcoma, Ewing sarcoma, and GCT were enrolled. The PD-L1 gene and protein expression were assessed by qRT-PCR and immunohistochemistry, respectively. ELISA and flow cytometry was used to detect cytokines and CD4/CD8 T cell percentages, respectively. A considerable increase in PD-L1 level was detected in bone tumor tissues at both gene and protein levels that was considerable in osteosarcoma and Ewing sarcoma. A positive correlation was detected regarding the PD-L1 and tumor metastasis and recurrence in osteosarcoma and Ewing sarcoma. The increased IFN-γ level was detected in patients with metastatic, and recurrent osteosarcoma tumors that were in accordance with the level of TGF-β in these samples. The simultaneous elevation of IFN-γ and TGF-β was detected in Ewing sarcoma and GCT, also the CD4 + /CD8 + ratio was decreased significantly in patients with osteosarcoma compared to GCT tumors. The elevated levels of PD-L1, TGF- β, and IFN-γ were associated with bone tumor severity that can provide insights into the possible role of this axis in promoting immune system escape, suppression, and tumor invasion.

Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders

Introduction: Non-malignant disorders (NMD) derive no benefit from graft-versus-host disease (GVHD) after allogeneic hematopoietic transplantation (HCT). Transplantation designed to optimize engraftment and immune reconstitution while minimizing GVHD and organ toxicities is desirable. Post-transplant cyclophosphamide (PTCy) decreases severe chronic GVHD risk in radiation-containing regimens for NMD when combined with serotherapy (anti-thymocyte globulin) (PMID: 22955919; PMID: 30500440). Abatacept effectively offsets GVHD following unrelated donor (URD) HCT (PMID: 33449816; PMID: 32813873). Based on these reports, NCT03128996 was developed for haploidentical transplantation in NMD after radiation-free reduced intensity conditioning (RIC) combining PTCy + Abatacept for GVHD prophylaxis. Serotherapy does not contribute to GVHD prophylaxis in this RIC approach. Outcomes focused on safety and GVHD- free donor engraftment in children with NMD and no better donor options. Method: Conditioning included alemtuzumab (day -22 to -19), fludarabine (day -8 to -4), melphalan (day -3) and thiotepa (day -4) as previously published (hydroxyurea prior to RIC was used in proliferative marrow disorders) (PMID: 32813873). Stem cell source was bone marrow (BM) or CD34-selected peripheral blood cells with a fixed CD3 cell dose of 1x10^6/kg recipient weight. GVHD prophylaxis included tacrolimus (day -1, with wean beginning 6-9 months post-HCT), PTCy on days +3 and +4, mycophenolate mofetil until day +28, and monthly abatacept doses until 13 months post-HCT. Survival, safety, donor chimerism, GVHD incidence, and incidence of post HCT infection were primary outcome measures. Results: Eleven patients 6 to 24 years old (median 9 years) underwent HCT for adrenoleukodystrophy ( 2), sickle cell disease (SCD) ( 6), aplastic anemia ( 1), second transplant for severe combined immunodeficiency ( 1) and STAT 5B gain-of-function mutation ( 1). Eight were trial participants and 3 treated according to trial guidelines. All patients tolerated abatacept infusions and engrafted with neutrophil recovery (>500/cu mm) at a median of 17 days (range 15-24 days). As of 7/31/2023, median follow up is 411 days (range 83-1979 days). The mean myeloid and T-cell chimerisms at D100 (n=10) and 1 year (n=6) were 97.8%+/- 5.3 and 96.3% +/- 6.4 and 98.6% +/- 3.3 and 95% +/-8.7, respectively. One patient with SCD has low myeloid engraftment (24%) at 7 months post-HCT (lymphoid 91%); a stem cell boost is planned after immune suppression with fludarabine/Cytoxan/ATG (PMID: 35798858). Viral reactivation was noted in 4 patients, none developed CMV disease or EBV post-transplant lymphoproliferation. One patient developed grade 1 acute GVHD. Of 6 evaluable patients, one developed localized chronic skin GVHD. This patient remains on systemic immune suppression beyond 13 months (ruxolitinib). The overall and GVHD-free survival at 1-year post HCT in evaluable patients (N=6) is 100 % and 83%, respectively. Conclusion: Promising preliminary results in this cohort support continuation of the trial with longer term follow-up. The effective suppression of GVHD without serious infectious complications in the first year post-HCT is encouraging. Virus reactivation was however noted early post-HCT and requires monitoring and prophylaxis. Incorporating abatacept into GVHD prophylaxis was successful in achieving desired outcomes; the phase 1 portion of the study is completed and the phase 2 trial and follow-up are ongoing.

Outcomes after RIC and Abatacept-Based Acute and Chronic Gvhd Prophylaxis in Allogeneic Transplantation for Sickle Cell Disease - Can Calcineurin Inhibitor Use be Curtailed?

Introduction: Sickle cell disease (SCD) progression can be curtailed by successful allogeneic transplantation from suitable donors. Allogenic transplantation with reduced intensity immune suppressive conditioning (RIC) from sibling or unrelated donors was considered acceptable with the availability of an Human Leucocyte Antigen (HLA)-matched (8/8 loci) or minimally mismatched (7/8) donor on NCT00920972 and in 2018 the study was modified to include abatacept for acute and chronic graft-versus-host disease (GVHD) prophylaxis based on the incidence of severe chronic GVHD noted (13-38%) and the benefits described with abatacept1-3. An interim review of trial results following the modification of GVHD prophylaxis is presented. Methods: Patients with symptomatic SCD who were <21 years of age were enrolled on appropriate study cohorts based on the level of donor match. Cohort 1 included HLA matched donors and cohort 3 included donors mismatched at 1 of 8 major HLA loci (-A, -B, -C, -DRB1) by high resolution typing. Conditioning included alemtuzumab (distal: day -22 to -19), fludarabine (days -8 to -4) and melphalan (day -3). Thiotepa (day -4) was included for mismatched donors. GVHD prophylaxis included tacrolimus (day -1 and tapered 6-9 months later), methotrexate (days +1, 3 and 6) and abatacept (days -1, +5, 14, 28, 60, 90, 180, 270 and 365)4. Though the half-life of the drug is ~30 days, the interval was adjusted after day 100 to every 90 days to curb allogeneic T cell proliferation following complete elimination of the drug. No previous data exists on this approach. Outcomes tracked were GVHD, mortality and graft rejection (GR) (<25% donor myeloid cells/disease recurrence) Results: Nine related donor transplants (4-18 years, median 9y) and 9 unrelated donor transplants (URD) (7-20 years, median 16y) (5 mismatched) were undertaken consecutively after the addition of abatacept to the standard GVHD regimen. The duration of follow-up ranged from 2-59 months (median 44m). GR was noted in 2 patients. One patient with primary GR subsequently rejected a second graft after myeloablative conditioning. Another patient with secondary GR received a CD34-selected boost post-ATG unsuccessfully but stabilized after a flu/cy/ATG regimen and another CD34-selected boost. The most recent engraftment analysis in 17/18 patients is 98% (range, 46 to 100) for myeloid and 94.5% (range, 56 to 100) for lymphoid lineage cells. No patient developed > grade 2 acute or any chronic GVHD in the MSD group. In the URD group 1 patient each developed >grade 2 aGVHD and extensive cGVHD. Of evaluable patients, one remains on systemic immune suppression therapy >18 months post-transplant. The only mortality noted was after 2 subsequent transplants in the patient with GR. Seventeen patients remain disease free post-transplant. Disease free survival (DFS) is 94%. GVHD-free-DFS is 89%. The incidence of viral reactivation was 65% and 17% before and after day +100 respectively. Immune reconstitution was noted to normalize beyond 6-9 months. Conclusion: Transplant is beneficial in SCD, and an expansion of donor sources can help to increase the number of patients rendered disease-free. GVHD risks preclude consideration of allogeneic transplantation. A GVHD-free cure rate of >88% despite risk factors such as age and HLA-mismatch following RIC and abatacept-based GVHD prophylaxis is encouraging for allogeneic transplantation options for children and adolescents with SCD. Long-term follow-up is in progress.