Current Trends in Gelatin-Based Drug Delivery Systems.

Gelatin is a highly versatile natural polymer, which is widely used in healthcare-related sectors due to its advantageous properties, such as biocompatibility, biodegradability, low-cost, and the availability of exposed chemical groups. In the biomedical field, gelatin is used also as a biomaterial for the development of drug delivery systems (DDSs) due to its applicability to several synthesis techniques. In this review, after a brief overview of its chemical and physical properties, the focus is placed on the commonly used techniques for the development of gelatin-based micro- or nano-sized DDSs. We highlight the potential of gelatin as a carrier of many types of bioactive compounds and its ability to tune and control select drugs' release kinetics. The desolvation, nanoprecipitation, coacervation, emulsion, electrospray, and spray drying techniques are described from a methodological and mechanistic point of view, with a careful analysis of the effects of the main variable parameters on the DDSs' properties. Lastly, the outcomes of preclinical and clinical studies involving gelatin-based DDSs are thoroughly discussed.

Analysis of healthcare workers' mental health during the COVID-19 pandemic: Evidence from a three-wave longitudinal study.

The "Healthcare workers' wellbeing [Benessere Operatori]" project is an exploratory longitudinal study assessing healthcare workers' mental health at three different time points over a 14-month period during the COVID-19 pandemic. We collected socio-demographic and work-related information and assessed the perceived social support, coping strategies, and levels of depression, anxiety, insomnia, anger, burnout, and PTSD symptoms. In total, 325 Italian healthcare workers (i.e. physicians, nurses, other healthcare workers, and clerks) participated in the first initial survey and either the second or third subsequent survey. Participants reported subclinical levels of psychiatric symptoms that remained mostly unchanged across time, except for an increase in stress, depression, state anger, and emotional exhaustion symptoms. Despite subclinical levels, healthcare workers' distress can adversely affect the quality of care, patient satisfaction, and medical error rates. Therefore, implementing interventions to improve healthcare workers' wellbeing is required.

The Experience of COVID-19 in a Sample of Gynecological Cancer Patients Undergoing Chemotherapy: A Focus on the Psychological Implications.

Cancer patients are at an increased risk of developing severe consequences due to the COVID-19 infection. However, psychological outcomes in this population have been overlooked in the literature. The present study aims to identify significant psychological differences between gynecological cancer patients undergoing chemotherapy before and during the pandemic. Additionally, we explore the correlations between COVID-19-related concerns and anxiety, depression, distress, and quality of life levels. Forty-two patients completed the STAI-Y, the EORTC QLQ-C30, the BDI II, the DT, and an ad-hoc questionnaire that investigated COVID-19-related concerns. The analyses did not show significant differences in the psychometric scales between the two groups, highlighting a considerable resilience against mental health and quality of life deterioration during the COVID-19 pandemic in gynecologic cancer patients. However, COVID-19-related concerns were positively associated with anxiety and inversely related to emotional functioning levels. These results emphasize the importance of a comprehensive patient care and the need to implement a multidisciplinary approach that includes psychological support in the treatment plan. Moreover, it is essential to encourage clear communication to convey comprehensive information about the impact of the pandemic on physical and psychological levels, as well as to offer psychoeducational tools to face the pandemic.

Dental arch form and interdental widths evaluation in adult Caucasian patients with obstructive sleep apnea syndrome.

OBJECTIVE: To evaluate the hypothesis that dental arch form and inter-canine, inter-premolar, and inter-molar widths differ between OSAS patients and non-snoring, non-apneic controls. METHODS: Dental digital models from 64 OSAS patients and 64 control subjects were used to obtain dental arch forms and to compare them between the two groups. Arch forms were extracted from the lower arch models using a professional graphics program and an orthodontic digital template. Through an orthodontic software, inter-molar, inter-premolar, and inter-canine widths were measured for both upper and lower arches. RESULTS: The dental arch forms distribution differed between OSAS patients and controls. OSAS patients had reduced inter-canine, inter-premolar, and inter-molar widths for both arches compared to controls. DISCUSSION: These results suggest that OSAS patients have narrower and more tapered arches than controls. Dental arch morphology and interdental widths differ between OSAS and control groups, supporting the hypothesis that they are an etiological factor.

From Serendipity to Rational Identification of the 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one Core as a New Chemotype of AKT1 Inhibitors for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 has emerged as the most interesting compound with IC50 = 1.99 ± 0.11 µM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one derivative T126 is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents.

Current status and future perspectives in targeted therapy of NPM1-mutated AML.

Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30-35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

SiCoDEA: A Simple, Fast and Complete App for Analyzing the Effect of Individual Drugs and Their Combinations.

The administration of combinations of drugs is a method widely used in the treatment of different pathologies as it can lead to an increase in the therapeutic effect and a reduction in the dose compared to the administration of single drugs. For these reasons, it is of interest to study combinations of drugs and to determine whether a specific combination has a synergistic, antagonistic or additive effect. Various mathematical models have been developed, which use different methods to evaluate the synergy of a combination of drugs. We have developed an open access and easy to use app that allows different models to be explored and the most fitting to be chosen for the specific experimental data: SiCoDEA (Single and Combined Drug Effect Analysis). Despite the existence of other tools for drug combination analysis, SiCoDEA remains the most complete and flexible since it offers options such as outlier removal or the ability to choose between different models for analysis. SiCoDEA is an easy to use tool for analyzing drug combination data and to have a view of the various steps and offer different results based on the model chosen.

The "Healthcare Workers' Wellbeing [Benessere Operatori]" Project: A Longitudinal Evaluation of Psychological Responses of Italian Healthcare Workers during the COVID-19 Pandemic.

BACKGROUND: COVID-19 forced healthcare workers to work in unprecedented and critical circumstances, exacerbating already-problematic and stressful working conditions. The "Healthcare workers' wellbeing (Benessere Operatori)" project aimed at identifying psychological and personal factors, influencing individuals' responses to the COVID-19 pandemic. METHODS: 291 healthcare workers took part in the project by answering an online questionnaire twice (after the first wave of COVID-19 and during the second wave) and completing questions on socio-demographic and work-related information, the Depression Anxiety Stress Scale-21, the Insomnia Severity Index, the Impact of Event Scale-Revised, the State-Trait Anger Expression Inventory-2, the Maslach Burnout Inventory, the Multidimensional Scale of Perceived Social Support, and the Brief Cope. RESULTS: Higher levels of worry, worse working conditions, a previous history of psychiatric illness, being a nurse, older age, and avoidant and emotion-focused coping strategies seem to be risk factors for healthcare workers' mental health. High levels of perceived social support, the attendance of emergency training, and problem-focused coping strategies play a protective role. CONCLUSIONS: An innovative, and more flexible, data mining statistical approach (i.e., a regression trees approach for repeated measures data) allowed us to identify risk factors and derive classification rules that could be helpful to implement targeted interventions for healthcare workers.

Socio-demographic and psychological factors associated with quality of life of women undergoing chemotherapy treatment for gynecological cancer.

PURPOSE: This research aimed to investigate the socio-demographic, clinical, and psychological variables predictive of a greater functioning and quality of life in patients with gynecological cancer after their first cycle of carboplatin and taxol-based chemotherapy. METHODS: The sample of the present research consisted of 104 patients. The European Organization on Research and Treatment of Cancer QLQ-C30, the State-Trait Anxiety Inventory-Form Y, and the Multidimensional Scale of Perceived Social Support were administered to each participant. RESULTS: The analyses showed that higher state anxiety levels predicted a lower role, emotional, and social functioning and a lower general quality of life. Higher trait anxiety levels and social support perceived from one's friends predicted a greater role functioning. Similarly, having a relationship predicted a greater physical, cognitive, and social functioning. On the contrary, the presence of relapsed cancer was negatively associated with these patients' quality of life. CONCLUSIONS: The present study highlighted the importance of identifying patients at higher risk of experiencing lower levels of functioning and worse general quality of life to implement tailored interventions from the beginning of treatment, thus improving the quality of life of these patients throughout the chemotherapy treatment.

Inhibition of the BMP pathway prevents development of Barrett's-associated adenocarcinoma in a surgical rat model.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

Germline GATA2 variant disrupting endothelial eNOS function and angiogenesis can be restored by c-Jun/AP-1 upregulation.

GATA2 is a transcription factor with key roles in hematopoiesis. Germline GATA2 gene variants have been associated with several inherited and acquired hematologic disorders, including myelodysplastic syndromes. Among the spectrum of GATA2 deficiency- associated manifestations thrombosis has been reported in 25% of patients, but the mechanisms are unknown. GATA2 was shown to be involved in endothelial nitric oxide synthase (eNOS) regulation and vascular development. We assessed eNOS expression and angiogenesis in patients with GATA2 deficiency. Platelets and blood outgrowth endothelial cells (BOEC) from GATA2 variant carriers showed impaired NO production and reduction of eNOS mRNA and protein expression and of eNOS activity. GATA2 binding to the eNOS gene was impaired in BOEC from GATA2-deficient patients, differently from control BOEC. GATA2 deficiency BOEC showed also defective angiogenesis, which was completely restored by treatment with the NO-donor Snitroso- N-acetylpenicillamine (SNAP). Atorvastatin, but not resveratrol, largely restored eNOS expression, NO biosynthesis and neoangiogenesis in GATA2-deficient BOEC by a mechanism involving increased expression of the eNOS transcription factor AP-1/c-JUN, replacing GATA2 when the latter is inactive. Our results unravel a possible thrombogenic mechanism of GATA2 mutations, definitely establish the regulation of eNOS by GATA2 in endothelial cells and show that endothelial angiogenesis is strictly dependent on the eNOS/NO axis. Given the ability of atorvastatin to restore NO production and angiogenesis by GATA2-deficient endothelial cells, the preventive effect of atorvastatin on thrombotic events and possibly on other clinical manifestations of the syndrome related to deranged angiogenesis should be explored in patients with GATA2 deficiency in an ad hoc designed clinical trial.

Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML.

Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non-exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases. Besides mutations in exons 9 (n = 1) and 11 (n = 1), novel exon 5 mutations were discovered (n = 3). Another exon 5 mutation was identified in an additional 141 patients with AML selected for wild-type NPM1 exon 12. Three NPM1 rearrangements (NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13 979 AML samples screened by cytogenetic/fluorescence in situ hybridization and RNA sequencing. Functional studies demonstrated that in AML cases, new NPM1 proteins harbored an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting AML-associated NPM1 genetic lesions. This study highlights the need to develop new assays for molecular diagnosis and monitoring of NPM1-mutated AML.

The "Healthcare Workers' Wellbeing (Benessere Operatori)" Project: A Picture of the Mental Health Conditions of Italian Healthcare Workers during the First Wave of the COVID-19 Pandemic.

During the last year, the COVID-19 outbreak put all the healthcare workers around the world at risk of physical and psychological sequelae. The general purpose of the present study was to assess the mental health of Italian healthcare workers during the COVID-19 outbreak and to identify high-risk groups. Here, we present results from the baseline assessment of the "Healthcare workers' wellbeing (Benessere Operatori)" project on a sample of 1055 healthcare workers. Participants completed the Depression Anxiety Stress Scale-21, the Insomnia Severity Index, the Impact of Event Scale-Revised, the State-Trait Anger Expression Inventory-2, and the Maslach Burnout Inventory. Healthcare workers who worked in COVID wards reported higher levels of anxiety, insomnia, post-traumatic stress, anger, and burnout, compared to those reported by the healthcare workers who worked in non-COVID wards. Moreover, nurses, both in COVID and non-COVID wards, were at higher risk of experiencing psychological distress compared to other groups of healthcare workers. These findings highlight the importance of implementing targeted psychological interventions for healthcare workers operating in COVID wards and nurses, who seem to be the most vulnerable categories.

Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML.

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.

CD123 Is Consistently Expressed on NPM1-Mutated AML Cells.

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34+CD38- leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34+CD38- leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies.

Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.

Knowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.

Personality traits and oral device: a new challenge to increase compliance with MAD therapy for OSAS and snoring.

Obstructive Sleep Apnea Syndrome (OSAS) is a respiratory syndrome and oral devices can be used for its treatment. This study aimed to evaluate the opinions of a generic subject about being treated by a dentist for a general health problem and the association between personality traits and the predisposition to use a MAD for the treatment of OSAS and snorting. One hundred and forty-eight participants were enrolled in the study and were asked to fill in the questionnaires. Personality traits were evaluated using NFC (Need for Closure), PER (openness to new experiences), STAI-Trait and STAI-Stat questionnaires (State-Trait Anxiety Inventory). The propensity to be treated with dental devices for a general health problem such as OSAS and snoring was evaluated with a specific questionnaire. Eight out of ten participants would accept to use dental device to be kept at night for the solution of a health problem or the treatment of a disease that does not affect the teeth. A positive opinion on device used to treat OSAS was associated with higher PER and lower Mad-related distress, while the opinion of usefulness of the device was positively associated with higher PER and STAI-Trait. A positive opinion about treatment of snorting and OSAS using dental devices was associated with higher PER, while lower STAI-Trait was associated with positive opinion on treatment of snorting using dental-devices. The results suggest that some personality traits are associated with the propensity to use MAD to treat a general pathology as OSAS.

Mutant NPM1 Maintains the Leukemic State through HOX Expression.

NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

microRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Antitumor Immune Response and Poor Outcomes of Patients.

BACKGROUND & AIMS: Immune checkpoint inhibition may affect growth or progression of highly aggressive cancers, such as esophageal adenocarcinoma (EAC). We investigated the regulation of expression of major histocompatibility complex, class 1 (MHC-I) proteins (encoded by HLA-A, HLA-B, and HLA-C) and the immune response to EACs in patient samples. METHODS: We performed quantitative polymerase chain reaction array analyses of OE33 cells and OE19 cells, which express different levels of the ATP binding cassette subfamily B member 1 (TAP1) and TAP2, required for antigen presentation by MHC-I, to identify microRNAs (miRNAs) that regulate their expression. We performed luciferase assays to validate interactions between miRNAs and potential targets. We overexpressed candidate miRNAs in OE33, FLO-1, and OACP4 C cell lines and performed quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses to identify changes in messenger RNA (mRNA) and protein expression; we studied the effects of cytotoxic T cells. We performed miRNA in situ hybridization, RNA-sequencing, and immunohistochemical analyses of tumor tissues from 51 untreated patients with EAC in the Netherlands. Clinical and survival data were collected for patients, and EAC subtypes were determined. RESULTS: We found OE19 cells to have increased levels of 7 miRNAs. Of these, we found binding sites for miRNA 125a (MIR125a)-5p in the 3' untranslated region of the TAP2 mRNA and binding sites for MIR148a-3p in 3' untranslated regions of HLA-A, HLA-B, and HLA-C mRNAs. Overexpression of these miRNAs reduced expression of TAP2 in OE33, FLO-1, and OACP4 C cells, and reduced cell-surface levels of MHC-I. OE33 cells that expressed the viral peptide BZLF1 were killed by cytotoxic T cells, whereas OE33 that overexpressed MIR125a-5p or MIR 148a along with BZLF1 were not. In EAC and nontumor tissues, levels of MIR125a-5p correlated inversely with levels of TAP2 protein. High expression of TAP1 by EAC correlated with significantly shorter overall survival times of patients. EACs that expressed high levels of TAP1 and genes involved in antigen presentation also expressed high levels of genes that regulate the adaptive immune response, PD-L1, PD-L2, and IDO1; these EACs had a poor response to neoadjuvant chemoradiotherapy and associated with shorter overall survival times of patients. CONCLUSIONS: In studies of EAC cell lines and tumor tissues, we found increased levels of MIR125a-5p and MIR148a-3p to reduce levels of TAP2 and MHC-I, required for antigen presentation. High expression of MHC-I molecules by EAC correlated with markers of an adaptive immune response and significantly shorter overall survival times of patients.