Deciphering cellular and molecular mechanism of MUC13 mucin involved in cancer cell plasticity and drug resistance.

There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.

Spiritual Coping: A Gateway to Enhancing Family Communication During Cancer Treatment.

The researchers examined the spiritual coping, family communication, and family functioning of 95 participants in 34 families by an online survey. Multilevel linear regression was used to test whether individuals' and families' higher endorsement of more use of spiritual coping strategies to deal with a member's cancer would be associated with higher scores on family communication and family functioning, and whether better communication would also be associated with higher family functioning scores. Results revealed that spiritual coping was positively associated with family communication, and family communication was positively associated with healthier family functioning. The researchers provide suggestions for further research.

Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer.

OBJECTIVE: Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro. This is a truncated, dominant negative form of Galectin-3, which is thought to act by blocking endogenous Galectin-3. METHODS: We produced a truncated, dominant-negative form of Galectin-3, namely Galetic-3C. Ovarian cancer cell lines and primary cells from ovarian cancer patients were treated with Galectin-3C, and growth, drug sensitivity, and angiogenesis were tested. RESULT: We show, for the first time, that Galectin-3C significantly reduces the growth, motility, invasion, and angiogenic potential of cultured OC cell lines and primary cells established from OC patients. CONCLUSIONS: Our findings indicate that Galectin-3C is a promising new compound for the treatment of ovarian cancer.

EXPRESS: Iron and Cardiovascular Health: A Review.

Iron is and essential element for the biological processes of living organisms, including the production of crucial oxygen-carrying proteins, formation of heme enzymes and playing roles in electron transfer and oxidation-reduction reactions. It plays a significant role in various cardiovascular functions, including bioenergetics, electrical activity, and programmed cell death.Minor deficiencies of iron have been found to have negative impact on cardiovascular function in patients with heart failure (HF). The contractility of human cardiomyocytes is impaired by iron deficiency (ID), which results in reduced mitochondrial function and lower energy production, ultimately leading to cardiac function impairment, contributing to significant morbidity and mortality in patients with HF.This review discusses iron homeostasis within the human body, as well as iron deficiency pathophysiology and its role in HF. Focusing on therapeutic approaches including iron supplementation and/or repletion in patients with ID and HF, comparing results from recent clinical trials.Intravenous (IV) iron therapy has shown promising results in treating ID in HF patients. Large, randomized trials and meta-analysis, like FAIR-HF, AFFIRM-AHF, IRONMAN, and HEART-FID have demonstrated the efficacy of IV iron supplementation with IV ferric carboxymaltose (FCM) or IV ferric derisomaltose in reducing hospitalizations and improving quality of life in patients with HFrEF, NYHA II-III. However, survival and mortality have demonstrated no improvement during acute exacerbations of HF or in outpatient management. The potential benefits of IV iron across the entire HF spectrum and its interaction with other HF therapies remain areas of interest for further research.

Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen.

The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine-matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation. Ovarian tumor antigen-specific CD4(+) T cells secrete high levels of IL-17 and show reduced expression of CTLA-4, PD-1, and Foxp3 following activation with IL-15/p38 inhibitor-treated DC. We further show that modulation of p38 MAPK signaling in DC is associated with reduced expression of B7-H1 (PD-L1), loss of indoleamine 2,3-dioxygenase activity, and increased phosphorylation of ERK 1/2 MAPK. These observations may allow the development of innovative DC vaccination strategies to boost Th17 immunity in ovarian cancer patients.

Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia.

Tumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T-ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand-independent signalling and/or prolonging Notch1 half-life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ-Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine receptors. Our results indicate that γ-Secretase inhibitor negatively regulates the transcription level of the CC chemokine receptors 5 and 9 in T-ALL cell lines and patients' primary leukaemia cells, leaving CXCR4 expression unaltered. The Notch pathway also controls CCR5- and CCR9-mediated biological effects, ie chemotaxis and proliferation. Furthermore, engaging CCR9 through CCL25 administration rescues proliferation inhibition associated with abrogation of Notch activity. Finally, through RNA interference we demonstrated that the oncogenic isoform in T-ALL, Notch1, plays a role in controlling CCR5 and CCR9 expression and functions. These findings suggest that Notch1, acting in concert with chemokine receptors pathways, may provide leukaemia cells with proliferative advantage and specific chemotactic abilities, therefore influencing tumour cell progression and localization.

Mast cells and the liver aging process.

It has now ascertained that the clinical manifestations of liver disease in the elderly population reflect both the cumulative effects of longevity on the liver and the generalized senescence of the organism ability to adjust to metabolic, infectious, and immunologic insults. Although liver tests are not significantly affected by age, the presentation of liver diseases such as viral hepatitis may be subtler in the elderly population than that of younger patients.Human immunosenescence is a situation in which the immune system, particularly T lymphocyte function, deteriorates with age, while innate immunity is negligibly affected and in some cases almost up-regulated.We here briefly review the relationships between the liver aging process and mast cells, the key effectors in a more complex range of innate immune responses than originally though.

What You See Is Not What You Get: Germ Cell Tumor Mimicking Disseminated Coccidioidomycosis.

We present the case of a 30-year-old man with no prior medical history who presented to the hospital with a myriad of symptoms such as shortness of breath, generalized weakness, lower limb weakness, and urinary retention. He was recently diagnosed with "disseminated coccidioidomycosis" by an outside provider on an outpatient basis and started on fluconazole orally. However, due to a lack of improvement and significant symptoms, he was sent to the hospital to initiate liposomal amphotericin B treatment. After a comprehensive workup, an alternative diagnosis was suspected and eventually confirmed as metastatic germ cell carcinoma. Due to the vast dissemination and his poor functional status despite chemotherapy initiation, the patient elected for palliative care and expired shortly after at hospice. This case demonstrates the similarity of clinical findings between disseminated infections and malignancies.

A Case of Disseminated Histoplasmosis From California, in the Setting of Secondary Hemophagocytic Lymphohistiocytosis: A Diagnostic Challenge.

Histoplasma capsulatum is a geographically specific dimorphic fungus that can cause a spectrum of diseases. While most cases are asymptomatic pulmonary infections, in severe cases, particularly in immunocompromised patients, disseminated disease can occur. Histoplasmosis in California is limited to only a few case reports. In this article, we describe a rare case of disseminated histoplasmosis in a non-endemic region presenting with diagnostically challenging symptomatology, including altered mental status, status epilepticus, septic shock, and bilateral adrenal masses.

Spurious Presentation of Pulmonary Kaposi Sarcoma as Unresolved Pneumonia Led to Fatal Outcome.

Acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) is an angioproliferative neoplasia caused by infection with human herpesvirus 8 (HHV-8). It typically presents with mucocutaneous involvement, but it can be disseminated. Initial presentation with primarily pulmonary KS is rare. We present a case of a 32-year-old male with untreated human immunodeficiency virus (HIV) diagnosed 1 year before presentation who developed progressively worsening cough and shortness of breath for 6 months. He was hospitalized twice and treated for unresolved pneumonia in an outside hospital. The patient concomitantly developed purplish nodules on his face, then the upper trunk, back, chest, and thighs bilaterally that gradually increased in size and number. Histopathology findings from skin lesions were consistent for KS. Bronchoscopy found multiple erythematous plaques throughout the tracheobronchial tree with telangiectasias and inflammation suggestive of pulmonary KS. His imaging findings and positive serum HHV-8 polymerase chain reaction (PCR) were consistent with disseminated KS. He started antiretroviral therapy (ART) to treat his HIV infection, followed by liposomal doxorubicin chemotherapy. But both ART and chemotherapy were interrupted due to adherence and insurance issues. The patient was readmitted with acute respiratory failure requiring mechanical ventilation with multiple vasopressors that led to the patient's demise. The late recognition of KS diagnosis and delayed treatment can lead to worse outcomes.

CDK1-mediated phosphorylation of Abi1 attenuates Bcr-Abl-induced F-actin assembly and tyrosine phosphorylation of WAVE complex during mitosis.

Coordinated actin remodeling is crucial for cell entry into mitosis. The WAVE regulatory complex is a key regulator of actin assembly, yet how the WAVE signaling is regulated to coordinate actin assembly with mitotic entry is not clear. Here, we have uncovered a novel mechanism that regulates the WAVE complex at the onset of mitosis. We found that the Bcr-Abl-stimulated F-actin assembly is abrogated during mitosis. This mitotic inhibition of F-actin assembly is accompanied by an attenuation of Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex. We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis. The Abi1 phosphorylated on serine 216 displayed greatly reduced tyrosine phosphorylation in the hematopoietic cells transformed by Bcr-Abl. Moreover, a phosphomimetic mutation of serine 216 to aspartic acid in Abi1 was sufficient to attenuate Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex and F-actin assembly. Ectopic expression of Abi1 with serine 216 mutations interfered with cell cycle progression. Together, these data show that CDK1-mediated phosphorylation of serine 216 in Abi1 serves as a regulatory mechanism that may contribute to coordinated actin cytoskeleton remodeling during mitosis.

Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer.

BACKGROUND: Prostate cancer (PC) is the second most common cancer in older men, after skin cancer. PC is difficult to diagnose because the prostate-specific antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments. Among presently available new treatments, immunotherapy is a promising approach. We investigated the expression of the cancer/testis antigen, AKAP-4, in PC patients to evaluate the possibility of exploiting AKAP-4 as a target for immunotherapy. METHODS: We analyzed normal prostate tissues, 15 patients with PC and the LnCAP PC cell line by immunohistochemistry. We tested AKAP-4 immunogenicity through indirect ELISA on sera from patients and healthy subjects, and we generated in vitro AKAP-4-specific cytotoxic lymphocytes from peripheral blood mononuclear cells. RESULTS: AKAP-4 was shown both at the cytoplasmic and surface levels of the LnCAP PC cell line. AKAP-4 was also highly expressed in PC cells from patients. We detected specific anti-AKAP-4 circulating immunoglobulins in AKAP-4 positive subjects. Using recombinant AKAP-4 loaded autologous dendritic cells, we generated AKAP-4-specific and HLA-I-restricted cytotoxic T lymphocytes able to kill PC cells in vitro. Further characterization indicated a Th-1 skewing in the cytokine secretion profile of these cells. CONCLUSIONS: We demonstrate the aberrant expression of AKAP-4 in PC, which will potentially be developed as a biomarker in PC. We provide evidence that AKAP-4 is a potential target for PC adoptive immunotherapy or anti-tumor vaccination.

Aging, cancer, and cancer vaccines.

World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people 1. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 2. Further, cancer-related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older 3. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression.

LECT-2 amyloidosis: what do we know?

Amyloidosis is a rare group of diseases characterized by abnormal folding of proteins and extracellular deposition of insoluble fibrils. It can be localized to one organ system or can have systemic involvement. The kidney is the most common organ to be involved in systemic amyloidosis often leading to renal failure and the nephrotic syndrome. The two most common types of renal amyloidosis are immunoglobulin light chain-derived amyloidosis (AL) and reactive amyloidosis (AA). A novel form of amyloidosis (ALECT2) derived from leukocyte chemotactic factor 2 (LECT-2) and primarily involving the kidneys was first described by Benson et al in 2008. The liver was subsequently identified as the second most common organ involved in ALECT2 amyloidosis. LECT-2 is a unique protein that can form amyloid deposits even in its unmutated form. Patients with ALECT2 present with minimal proteinuria in contrast to other forms of amyloidosis especially AL and AA. They may present with slightly elevated serum creatinine. Nephrotic syndrome and hematuria are rare. ALECT2 can be found in association with other types of amyloidosis as well as malignancies or autoimmune diseases. ALECT2 may be confused with amyloidosis associated with light and heavy chain monoclonal gammopathy if the immunofluorescence is positive with anti-light chain and anti-AA sera. The other organs involved are the duodenum, adrenal gland, spleen, prostate, gall bladder, pancreas, small bowel, parathyroid gland, heart, and pulmonary alveolar septa, but consistently uninvolved organs included brain and fibroadipose tissue. A renal biopsy along with characteristic features found on immunohistochemistry and mass spectrometry is diagnostic of ALECT2. ALECT2 should be suspected when all markers for AL and AA are negative. Proper diagnosis of ALECT2 can determine need for supportive care versus more aggressive interventions.

Immune Thrombocytopenia following COVID-19 Vaccine.

Several vaccines have been developed and are being administered against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Common side effects include fever, chills, headache, myalgia, and soreness at the injection site. However, some rare adverse effects have also been reported. We present a case of induced thrombocytopenia presenting with petechiae and mucosal bleeding which developed as an adverse response after first-dose administration of the Moderna COVID-19 vaccine.

Two Cases of Pelvic Diffuse Large B-Cell Lymphoma.

Primary diffuse large B-cell lymphoma presenting as an extranodal site in the pelvis is rare and can mimic a gynecological malignancy. Although management for diffuse large B-cell lymphoma is standardized and curative, prognosis depends on timely diagnosis and therapy. Diagnosis can be challenging as patients lack classical symptoms of fever, night sweats, weight loss, and lymphadenopathy associated with lymphoma. A multidisciplinary approach is recommended to diagnose and treat judiciously. In this article, we present cases of 2 females who presented with pelvic masses with initial suspicion of a gynecological malignancy but were ultimately diagnosed as diffuse large B-cell lymphoma of the pelvis and managed accordingly.

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4.

BACKGROUND: Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease. METHODS: Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4. RESULTS: Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45. CONCLUSIONS: We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.

Non-Hodgkin's Plasmablastic Lymphoma as Initial Presentation of Human Immunodeficiency Virus.

Plasmablastic lymphoma (PBL) is a subtype of non-Hodgkin's lymphoma that manifests in patients with the diagnosis of human immunodeficiency virus (HIV), more prominently in the head, neck, and oral mucosal region. The diagnosis of this rare lymphoma serves as a concomitant diagnosis of acquired immunodeficiency syndrome. The case is of a 33-year-old previously healthy male, with an unknown diagnosis of HIV with a painful right mandibular mass. He was subsequently diagnosed with PBL and HIV. This case of PBL illustrates the importance of linking a rare and potentially life-threatening diagnosis as a possible first manifestation of HIV.

Locus Minoris Resistentiae: Two Cases of Malignant Metastasis and Review of Literature.

Locus minoris resistentiae refers to a region of decreased resistance within the body. This occurs from changes to the microenvironment secondary to previous trauma and results in increased vulnerability. As a result, infection, inflammatory processes, and malignancy may localize to this area. In this article, we describe 2 unique cases of malignancy, primary prostate carcinoma and serous carcinoma of the ovary, both of which disseminated to sites of prior trauma. We review the available literature, discuss proposed pathophysiology, and highlight the need for further investigations along with increased clinician awareness.