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In approximately half of the recurrent spontaneous abortion (RSA) cases, the underlying cause is unknown. However, most unexplained miscarriages are thought to be linked to immune dysfunction. This review summarizes the current evidence regarding the immunological evaluations of patients with RSA, with potential implications for clinical research. The immune system plays a crucial role in the successful outcome of pregnancy, as it tolerates the semi-allogeneic fetus while offering protection to both the mother and fetus from pathogens. The maternal-fetal interface is the place where the crosstalk between various immune cells such as macrophages, dendritic cells, natural killer (NK) cells, and T cells takes place. An adequate balance is required between these immune cells for pregnancy to progress. In RSA, a dysregulation between these immune players is witnessed. For example, in RSA, NK cells are not increased but also undergo a change in their activity, manifested as cytotoxic decidual NK. Similarly, regulatory T cells, which are crucial for fostering a tolerant immune environment, are decreased in RSA women. Similarly, imbalances between T-helper (Th1, Th2, Th17) cell subsets have been implicated in RSA. Furthermore, the imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes has been documented, with studies indicating a predominance of M1 macrophages in RSA patients. Targeting immune imbalances with therapies such as immunoglobulin administration, TNF inhibitors, and anticoagulants may improve pregnancy outcomes in women with RSA.

Pregnancy is a highly regulated biological phenomenon that involves the development of a semi-allogeneic fetus inside the uterus of the mother. The maternal-fetal interface is a critical junction where communication takes place between the fetal and maternal immune systems, which determine the outcome of the pregnancy. The interface is composed of the decidua and placenta. The main cells present at the maternal-fetal interface include invading trophoblasts, maternal immune cells, and decidual stromal cells. Although maternal tolerance is crucial for maintaining a successful pregnancy, the role of the placenta in pregnancy is also important. Dysregulation of the placenta leads to various placenta-mediated complications, such as preeclampsia, intrauterine growth restriction, and placental abruption. Although the exact mechanism involving these complications is unclear, research has elucidated various factors involved in these pregnancy disorders. This review aimed to provide a summary of the maternal-fetal interface and immune mechanisms involved in placenta-mediated complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Andreescu et al.)

Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a heterogenous group of acquired clonal conditions. The three classic MPNs are essential thrombocythemia (ET), myelofibrosis (PMF), and polycythemia vera (PV). All subtypes of MPN are associated with both thrombotic and bleeding complications. There are four risk categories for thrombosis in MPN patients: age, thrombosis history, and JAK -2 mutation. They are further classified as very low, low, intermediate, and high risk. The genetic landscape of MPN is fascinating and complex like all myeloid disorders. Bleeding risk can be assessed through leukocytosis, thrombocytosis, acquired von Willebrand syndrome (AVWS), and a previous history of bleeding in a patient. Risk assessment and perioperative management are important aspects of improving the quality of life and preventing complications in surgeries. Preoperative management includes a risk assessment of venous thromboembolism, use of appropriate pharmacological treatment, platelet count control, and correction and cardiovascular risk factors. This review summarizes the assessment of bleeding and thrombosis risk for patients with MPNs scheduled for surgery. Furthermore, this review discusses various tools that can be used to identify MPN patients at risk of thrombosis prior to surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Andreescu et al.)

With the advent of COVID-19, the number of patients diagnosed with mucormycosis has increased, especially in developing countries. The reason behind this increase is that COVID-19 causes hypoxia that promotes the growth of fungus. To identify the association between mucormycosis and COVID-19, in critically ill or immunocompromised COVID-19 patients. The literature included in the review was researched from October 1, 2021, to November 1, 2022, by using the Google Scholar database as the search engine. Of the 20 articles included, there were 4 case reports, 2 case series, 10 narrative reviews, and 4 quantitative studies. Mucormycetes growth is caused by several factors, including hyperglycemia owing to previously existing diabetes or excessive use of steroids, increased ferritin levels owing to the inflammatory cascade initiated by COVID-19, and immunosuppression caused by the use of steroids or other immunosuppressive therapy. Reduced white-cell count and activity in COVID-19 leads to increased germination of fungal spores hence developing a catastrophic picture of rhinocerebral mucormycosis. Considering that the hematological patient is frequently treated with cortisone, immunosuppressed due to the underlying condition, but also through the administered therapy, the association with a possible diabetes makes this patient susceptible to developing rhinocerebral mucormycosis during COVID-19 infection. Despite being severe, the association between mucormycosis and COVID-19 is specific and treatable. Development of mucormycosis in hematological patients suffering from severe COVID-19 disease is dangerous, yet not compulsory and can be prevented. Using a common steroid-dose protocol with hyperbaric oxygen and necessary preventive measure reveals the disease as a superadded infection. Hypoxia, poor glycemic control and overuse of steroids or immunosuppressive drugs cause it., Competing Interests: The authors report no conflicts of interest in this work. This research received no external funding., (© 2024 Andreescu et al.)

The malfunctioning of human leukocyte antigen (HLA) class I antigens has a substantial negative impact on the effectiveness of leukemia treatment, particularly in the development of immunotherapies that rely on T-cell activation. HLA-G, a molecule that suppresses the immune response, plays a role in repressing the activation and proliferation of T cells, natural killer cells, and antigen-presenting cells. The expression of HLA-G is associated with various pathological conditions. Tumor cells exploit the immune evasion capabilities of HLA, allowing them to evade detection and elimination by the immune system. Understanding and modifying the HLA molecules is crucial for the advancement of innovative immunotherapies targeting chronic lymphocytic leukemia. Numerous mechanisms have been investigated to elucidate how HLA facilitates tumor evasion in patients with chronic lymphocytic leukemia and other malignancies. These mechanisms include inhibiting immune cell cytolysis, altering cytokine production levels, promoting immune cell programmed cell death, and impairing chemotaxis. This review provides a comprehensive overview of immune evasion mediated by HLA and its implications for targeted therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Andreescu et al.)

Concurrent infections in hematological malignancies (HM) are major contributors to adverse clinical outcomes, including prolonged hospitalization and reduced life expectancy. Individuals diagnosed with HM are particularly susceptible to infectious pathogens due to immunosuppression, which can either be inherent to the hematological disorder or induced by specific therapeutic therapies. Over the years, the treatment paradigm for HM has witnessed a tremendous shift from broad-spectrum treatment approaches to more specific, targeted therapies. Even now, the therapeutic landscape of HM is constantly evolving due to the advent of novel targeted therapies and enhanced utilization of these agents for treatment purposes. By initiating unique molecular pathways, these agents hinder the proliferation of malignant cells, consequently affecting innate and adaptive immunity, which increases the risk of infectious complications. Due to the complexity of novel targeted therapies and their associated risk of infection, it often becomes a daunting task for physicians to maintain updated knowledge in their clinical practice. The situation is further aggravated by the fact that most of the initial clinical trials on targeted therapies provide inadequate information to conclude the associated risk of infection. In such a scenario, a cumulative body of evidence is paramount for guiding clinicians regarding the infectious complications that can arise following targeted therapies. In this review, I summarize the recent knowledge on infectious complications arising in targeted therapies for HM., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Andreescu et al.)

Epigenetic alterations are heritable and enduring modifications in gene expression that play a pivotal role in immune evasion. These include alterations to noncoding RNA, DNA methylation, and histone modifications. DNA methylation plays a crucial role in normal cell growth and development but alterations in methylation patterns such as hypermethylation or hypomethylation can enable tumor and viral cells to evade host immune responses. Histone modifications can also inhibit immune responses by promoting the expression of genes involved in suppressing normal immune function. In the case of T-cell lymphoma, adult T-cell lymphomas (ATL) also undergo immune evasion through the exceptional function of its accessory and regulatory genes. Epigenetic therapies are emerging as a promising adjunct to traditional immunotherapy and chemotherapy regimens. Clinical trials are currently investigating the use of epigenetic therapies in combination with immunotherapies and chemotherapies for more effective treatment of ATL and other cancers. This review highlights epigenetic alterations that are widely found in T-cell malignancies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Andreescu et al.)

Stem cell transplant proved its efficacy in increasing the survival rate among young patients diagnosed with hematological malignancies. A transplant conditioning regimen is particularly destructive on the genital system, often determining premature ovarian failure, accompanied by vulvovaginal atrophy and sexual dysfunctions. The aims of the present study were, first, to evaluate sexual dysfunctions among transplanted women, using clinical examination and the female sexual function index (FSFI), and second, to determine their impact on a couple's relationship. A prospective observational comparative study was performed and included 38 patients who underwent allogenic stem cell transplant (SCT) procedures for different hematological malignancies and 38 healthy patients (control group). This study included baseline evaluation, one-year, and three-year follow-up visits. In addition to anamnesis and medically obtained information, FSFI was evaluated to determine the impact of gynecological damage in a subjective manner. In the study group, vulvovaginal atrophy was diagnosed in 76.32%, with subsequent sexual dysfunctions in 92.10% of patients, based on FSFI scoring. Even though the results improved throughout the study, at the last visit, mild vulvovaginal atrophy was diagnosed in 81.58% of patients, and the FSFI score was abnormal for 21.05%. When compared to the control group, both sexual dysfunctions and FSFI results were considerably impaired, with statistical significance. There is a confirmed negative impact of sexual dysfunctions and self-declared FSFI on couple/marital status and couple relationships, with statistical significance, at the last visit. In conclusion, anatomical, functional, and psychological difficulties are a reality of long-term survivors after a stem cell transplant. They should be addressed and assessed equally to other medical conditions, as they may determine serious consequences and impact the sexual quality of life and the couple's relationship.

Antibiotic therapy is a cornerstone of modern medicine, yet the development of antibiotic resistance threatens to render these therapies ineffective. The gut microbiota, a complex ecosystem of microorganisms residing in the gastrointestinal tract, plays a critical role in modulating antibiotic efficacy and resistance. This review delves into the intricate relationship between gut microbiota, antibiotic therapy, and resistance and discusses the potential applications of gut microbiota research in guiding personalized antibiotic therapy and resistance mitigation strategies. Recent advancements in metagenomics, metatranscriptomics, and metabolomics have demonstrated the potential for tailored antibiotic regimens that minimize collateral damage to commensal bacteria and reduce the risk of resistance. Adjuvant therapies, such as probiotics, prebiotics, and synbiotics, have shown promise in restoring gut microbial balance and mitigating the adverse effects of antibiotic therapy. We address the challenges associated with this emerging field, including the need for standardized methodologies, ethical considerations, and interdisciplinary collaboration. With continued interdisciplinary collaboration and the implementation of standardized methodologies, gut microbiota research can contribute to the global fight against antibiotic resistance and improve patient outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Andreescu et al.)

Cardiovascular diseases (CVD) have emerged as a common and serious complication of cancer treatment, particularly in patients undergoing cardiotoxic therapies. Over the last few years, the medical community has become increasingly aware of the potential for cardiotoxicity resulting from cancer treatments involving chemotherapy, targeted therapies, and radiation therapy. This recognition is due to the significant risk of morbidity and mortality in cancer patients and survivors resulting from such treatment-induced cardiovascular damage. While the cardiotoxic effects of chemotherapy and targeted therapy have been discussed in medical literature, only a limited number of studies have explored the role of serum biomarkers in cardiological risk stratification. In recent years, serum biomarkers have emerged as a valuable tool for assessing and managing cardiotoxicity in patients with hematological malignancies. This review article provides a summary of the current state of knowledge on the usefulness of biomarkers in managing cardiotoxicity resulting from different targeted therapies throughout the cancer care continuum. Although cardiac biomarkers have demonstrated potential in identifying subclinical cardiotoxicity and tracking the response to cardioprotective treatments, further research is necessary to determine optimal biomarkers and surveillance strategies. The incorporation of cardiac biomarkers into clinical practice in patients undergoing targeted therapies could potentially lead to improved long-term cardiovascular outcomes in cancer patients and survivors., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Andreescu et al.)

The tolerance of the immune system for the semi-allogeneic embryo is promoted by several factors and the cells involved in the immune system and factors in the mother during pregnancy. The dysregulation of the immune responses between the mother and fetus is a risk factor that raises the likelihood of rejection of the embryo and reproductive failure. To safeguard embryos and prevent immunological attacks, it is critical to suppress immunological rejection and encourage immunological tolerance. Based on current medical literature, it seems that immune cell management through immunosuppressive therapies can address reproductive failures. Immunosuppressive treatment has demonstrated encouraging results in terms of enhancing outcomes related to pregnancy and rates of live birth by regulating the immune responses of mothers and positively impacting the reproductive processes of humans. Currently, there is scarcity of high-quality data regarding the safety and efficacy of immunosuppressive therapies for children and mothers. Therefore, it is important to exercise caution while selecting use of any immunosuppressive therapy in pregnancy. This mini review provides a comprehensive overview of the existing literature regarding the impact of Calcineurin Inhibitors and anti-TNF treatment on improving the live birth rate following embryo transfer., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Andreescu.)

Concurrent infections in hematological malignancies (HM) are major contributors to adverse clinical outcomes, including prolonged hospitalization and reduced life expectancy. Individuals diagnosed with HM are particularly susceptible to infectious pathogens due to immunosuppression, which can either be inherent to the hematological disorder or induced by specific therapeutic strategies. Over the years, the treatment paradigm for HM has witnessed a tremendous shift, from broad-spectrum treatment approaches to more specific targeted therapies. At present, the therapeutic landscape of HM is constantly evolving due to the advent of novel targeted therapies and the enhanced utilization of these agents for treatment purposes. By initiating unique molecular pathways, these agents hinder the proliferation of malignant cells, consequently affecting innate and adaptive immunity, which increases the risk of infectious complications. Due to the complexity of novel targeted therapies and their associated risks of infection, it often becomes a daunting task for physicians to maintain updated knowledge in their clinical practice. The situation is further aggravated by the fact that most of the initial clinical trials on targeted therapies provide inadequate information to determine the associated risk of infection. In such a scenario, a cumulative body of evidence is paramount in guiding clinicians regarding the infectious complications that can arise following targeted therapies. In this review, I summarize the recent knowledge on infectious complications arising in the context of targeted therapies for HM.

Tumor growth and metastasis are reliant on intricate interactions between the host immune system and various counter-regulatory immune escape mechanisms employed by the tumor. Tumors can resist immune surveillance by modifying the expression of human leukocyte antigen (HLA) molecules, which results in the impaired presentation of tumor-associated antigens, subsequently evading detection and destruction by the immune system. The management of chronic lymphocytic leukemia (CLL) is based on symptom severity and includes various types of targeted therapies, including rituximab, obinutuzumab, ibrutinib, acalabrutinib, zanubrutinib, idelalisib, and venetoclax. These therapies rely on the recognition of specific peptides presented by HLAs on the surface of tumor cells by T cells, leading to an immune response. HLA class I molecules are found in most human cell types and interact with T-cell receptors (TCRs) to activate T cells, which play a vital role in inducing adaptive immune responses. However, tumor cells may evade T-cell attack by downregulating HLA expression, limiting the efficacy of HLA-dependent immunotherapy. The prognosis of CLL largely depends on the presence or absence of genetic abnormalities, such as del(17p), TP53 point mutations, and IGHV somatic hypermutation status. These oral targeted therapies alone or in combination with anti-CD20 antibodies have replaced chemoimmunotherapy as the primary treatment for CLL. In this review, we summarize the current clinical evidence on the impact of HLA- and cytokine-type responses on outcomes after targeted therapies currently used to treat CLL.

Immune tolerance at the feto-maternal interface is crucial for the growth of the semi-allograft fetus in the womb. The outcome of pregnancy is dependent on a fine balance between various immunological forces. For a long time, the potential role of the immune system in pregnancy disorders has remained enigmatic. Current evidence has revealed that natural killer (NK) cells are the predominant immune cell population in the uterine decidua. NK cells cooperate with T-cells to provide an optimal microenvironment for the growth of the developing fetus by producing cytokines, chemokines, and angiogenic factors. These factors support trophoblast migration and angiogenesis which regulates the process of placentation. NK cells differentiate between "self" and "non-self" through their surface receptors known as killer-cell immunoglobulin-like receptors (KIRs). They induce immune tolerance through communication via their KIR and fetal human leucocyte antigens (HLA). KIRs are surface receptors of NKs that comprise both activating and inhibiting receptors. Due to the wide diversity manifested by its genes, the KIR repertoire is different in each individual. Significant evidence has implicated KIRs in recurrent spontaneous abortion (RSA); however, maternal KIR gene diversity in RSA is still unclear. Research has shown that immunological aberrancies including activating KIRs, NK abnormalities, and T cell downregulation are risk factors for RSA. In this review, we discuss relevant data from experimental studies on NK cell abnormalities, KIR, and T-cells in the incidence of recurrent spontaneous abortion.

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive mature T-cell malignancy caused by the human T lymphoma virus I (HTLV-I) affecting 3-5% of HTLV-1 carriers and is usually diagnosed in endemic regions. Romania is a region with high prevalence of HTLV-1 infection and ATLL and with low median age at diagnosis for aggressive types. We performed a retrospective analysis of post-transplant outcome in the first Romanian patients with ATLL receiving hematopoietic stem cell allotransplant. The study population included eight patients (three males, five females), with median age of 39.5 (range 26-57), with acute (one case) and lymphoma type (seven cases) that received peripheral stem cells (PBSC) from matched related (MRD) and unrelated donors (MUD) after reduced intensity conditioning. Graft versus host disease (GVHD) developed in six patients. Relapse occurred in four cases (50%) at a median time of 5-months post-transplant. Six patients died: four cases with disease-related deaths and two patients with GVHD-related deaths. The median survival post-transplant was 19.5 months (range 2.3-44.2 months). The post-transplant survival at 1-year was 62.5%, at 2-years 50%, and at 3-years 37.5%. In our opinion allogeneic transplant improves outcome in aggressive type ATLL.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN., (© 2017 Wiley Periodicals, Inc.)