Fungal Volatile Organic Compounds: More Than Just a Funky Smell?

Many volatile organic compounds (VOCs) associated with industry cause adverse health effects, but less is known about the physiological effects of biologically produced volatiles. This review focuses on the VOCs emitted by fungi, which often have characteristic moldy or "mushroomy" odors. One of the most common fungal VOCs, 1-octen-3-ol, is a semiochemical for many arthropod species and also serves as a developmental hormone for several fungal groups. Other fungal VOCs are flavor components of foods and spirits or are assayed in indirect methods for detecting the presence of mold in stored agricultural produce and water-damaged buildings. Fungal VOCs function as antibiotics as well as defense and plant-growth-promoting agents and have been implicated in a controversial medical condition known as sick building syndrome. In this review, we draw attention to the ubiquity, diversity, and toxicological significance of fungal VOCs as well as some of their ecological roles.

DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.

Gender-Discordant Monochorionic-Diamniotic Twins Both With 45,X/46,X, Idic(Y) Mosaicism and a Novel Deletion Within the TBC1D5 Gene.

The occurrence of monochorionic diamniotic twins with sex discordance is a very rare phenomenon. We present a case of spontaneously conceived gender-discordant monochorionic diamniotic twins born to a 23-year-old female, both twins demonstrating similar blood karyotype 45,X/46,X, idic(Y) and a novel 99 kb mutation at 3p24.3 involving exons 15-16 of transcript NM_001134381.1 of the Tre-2/Bub2/Cdc16 Domain Family Member 5 (TBC1D5) gene. The male twin showed no anatomic abnormalities and pelvic ultrasound revealed descended gonads. The female twin had a horseshoe-shaped kidney, normal uterus, and intra-abdominal gonads. The blood karyotype and microarray studies revealed similar distribution of X and isodicentric Y chromosome along with a novel genetic mutation which has not been previously reported. Our case findings not only report Turner syndrome mosaicism with a novel genetic mutation but also stress the importance of clinical follow-up of twins in order to evaluate the functional abnormalities associated with isodicentric Y chromosomes including germ cell tumors.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration.

Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism.

Volatile organic compounds from fungi isolated after hurricane katrina induce developmental defects and apoptosis in a Drosophila melanogaster model.

In previous work, our laboratory developed a Drosophila model for studying the adverse effects of fungal volatile organic compounds (VOCs) emitted by growing cultures of molds. In this report, we have extended these studies and compared the toxic effects of fungal VOCs emitted from living cultures of four molds isolated after Hurricane Katrina from a flooded home in New Orleans. Strains of Aspergillus, Mucor, Penicillium, and Trichoderma were grown with wild-type larvae and the toxic effects of volatile products on the developmental stages of Drosophila larvae were evaluated. Furthermore, heterozygous mutants of Drosophila carrying the apoptotic genes, reaper and dronc, were used to assess the role of apoptosis in fungal VOCs mediated toxicity. Third-instar larvae of Drosophila carrying these apoptotic genes were exposed to fungal VOCs emitted from growing mold cultures for 10 days. The larval strains carrying apoptopic genes survived longer than the control wild type larvae; moreover, of those that survived, heterozygous reaper and dronc strains progressed to pupae and adult phases more rapidly, suggesting that fungal VOCs may induce apoptotic changes in flies. These data lend support to the use of Drosophila as an inexpensive and genetically versatile toxicological model to investigate the mechanistic basis for some of the human illnesses/symptoms associated with exposure to mold-contaminated indoor air, especially after hurricanes.

Drosophila melanogaster as a model to characterize fungal volatile organic compounds.

Fungi are implicated in poor indoor air quality and may pose a potential risk factor for building/mold related illnesses. Fungi emit numerous volatile organic compounds (VOCs) as alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. The toxicity profile of these VOCs has never been explored in a model organism, which could enable the performance of high throughput toxicological assays and lead to a better understanding of the mechanism of toxicity. We have established a reductionist Drosophila melanogaster model to evaluate the toxicity of fungal VOCs. In this report, we assessed the toxicity of fungal VOCs emitted from living cultures of species in the genera, Trichoderma, Aspergillus, and Penicillium and observed a detrimental effect on larval survival. We then used chemical standards of selected fungal VOCs to assess their toxicity on larval and adult Drosophila. We compared the survival of adult flies exposed to these fungal VOCs with known industrial toxic chemicals (formaldehyde [37%], xylene, benzene, and toluene). Among the tested fungal VOC standards, the compounds with eight carbons (C8) caused greater truncation of fly lifespan than tested non-C8 fungal VOCs and industrial toxins. Our data validate the use of Drosophila melanogaster as a model with the potential to elucidate the mechanistic attributes of different toxic VOCs emitted by fungi and also to explore the potential link between reported human illnesses/symptoms and exposure to water damaged and mold contaminated buildings.

Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell.

Lung disorders such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive lung disease (COPD), and interstitial lung disease (ILD) show a few common threads of pathogenic mechanisms: inflammation, aberrant immune activity, infection, and fibrosis. Currently no modes of effective treatment are available for ILD or emphysema. Being anti-inflammatory, immunomodulatory, and regenerative in nature, the administration of mesenchymal stem cells (MSCs) has shown the capacity to control immune dysfunction and inflammation in the lung. The intravenous infusion of MSCs, the common mode of delivery, is followed by their entrapment in lung vasculature before MSCs reach to other organ systems thus indicating the feasible and promising approach of MSCs therapy for lung diseases. In this review, we discuss the mechanistic basis for MSCs therapy for asthma, ARDS, COPD, and ILD.

Hematological entities with plasmacytic differentiation: a case report.

INTRODUCTION: Plasmacytoma, a localized tumor of monoclonal plasma cells without any clinical, radiological or physical evidence of plasma cell neoplasm (PCN), is a rare entity that accounts for 1% of PCN. Immunoglobulin M (IgM) extramedullary plasmacytoma of mediastinal region has never been reported and is a diagnostic challenge considering other differential diagnoses. CASE PRESENTATION: We present the case of a 51-year-old African-American female with progressively increasing cough, dyspnea, and dysphagia for 6 months with a computed tomography (CT) scan revealing a subcarinal mass. The histopathological analysis of the mass reveals a diagnosis of lymphoma with plasma cell differentiation, with a differential of lymphoplasmacytic lymphoma and plasma cell neoplasm. The lymphoma panel via next-generation sequencing (NGS) and a myeloma-targeted fluorescent in situ hybridization (FISH) panel confirmed the diagnosis of IgM extramedullary plasmacytoma, an entity of rare occurrence. Treatment with radiation led to complete regression of the plasmacytoma with normal blood work-up. CONCLUSIONS: This report describes the challenges of diagnosing IgM extramedullary plasmactyoma. Our case report highlights the importance of cytogenetics and NGS in establishing a correct diagnosis that indeed has prognostic and therapeutic implications.

A model to evaluate the cytotoxicity of the fungal volatile organic compound 1-octen-3-ol in human embryonic stem cells.

Microbial growth in damp indoor environments has been correlated with risks to human health. This study was aimed to determine the cytotoxicity of 1-octen-3-ol ("mushroom alcohol"), a major fungal volatile organic compound (VOC) associated with mushroom and mold odors. Using an airborne exposure technique, human embryonic stem cells were exposed for 1 h to different concentrations (0-1,000 ppm) of racemic 1-octen-3-ol and its enantiomers, (R)-(-)-1-octen-3-ol and (S)-(+)-1-octen-3-ol. Cytotoxicity was assayed using both the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and the fluorescently tagged Calcein AM-mediated "live and dead" assay. Racemic 1-octen-3-ol and (S)-(+)-1-octen-3-ol exhibited greater cytotoxicity to the undifferentiated human cell line H1 than did (R)-(-)-1-octen-3-ol. The inhibition concentration 50 (IC(50)) values assessed by the MTS assay for racemic 1-octen-3-ol, (S)-(+)-1-octen-3-ol and (R)-(-)-1-octen-3-ol were, respectively, 109, 98, and 258 ppm. These IC(50) values were 40-80-fold lower than that of vapor phase toluene, an industrial chemical used as a positive control in this study. Our report pioneers the modeling of human embryonic stem cells as an in vitro approach to screen the potential toxicity of fungal VOCs. Human embryonic stem cells exposed to 1-octen-3-ol, and its enantiomers in the vapor phase showed more cytotoxicity than those exposed to toluene.

A Rare Case of a Translocation-Associated Perivascular Epithelioid Cell Neoplasm (PEComa).

A perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm composed of perivascular epithelioid cells with distinctive histologic, immunohistochemical, and genetic features. PEComas arising from various anatomical sites have been reported, but gastrointestinal PEComas are extremely rare entities. Here, we discuss the clinical and pathological features of a gastrointestinal PEComa with a transcription factor E3 (TFE3) translocation in a 17-year old adolescent male with a clinical presentation of abdominal pain and gastrointestinal bleeding. Our case report provides insight into this rare entity as well as discusses the pathophysiological aspects of TFE3-SFPQ-associated GI PEComas and their management.

An Aggressive Presentation of Mantle Cell Lymphoma With Unique Molecular Features.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) with a dismal prognosis. The pathogenesis of MCL is complex and involves molecular alterations in various genes and pathways including the regulatory elements of the cell cycle machinery and senescence, DNA damage response pathways, and cell survival signals. Currently, Mantle Cell Lymphoma International Prognostic Index (MIPI) score and proliferative gene markers. TP53 and CDKN2A alterations are being used for the prognosis of MCL patients. The molecular profiling performed with various expression studies has paved the way for the identification of novel molecular targets and novel biomarkers not only aid in the diagnosis and prognosis of MCL but also predict the clinical outcome and prognosis. Our patient is a 74-year-old male who came for urinary complaints and routine blood work and revealed leukocytosis and lymphocytosis with abdominal and pelvic lymphadenopathies. Further work-up confirmed the diagnosis of MCL involving peripheral blood, bone marrow, and colon. In our patient, due to aggressive presentation, next generation sequencing was performed to understand the genetic aberrations relevant for MCL. In addition to known markers, we identified genetic mutations in FAT1, IKZF3, and TRAF2. which have never been reported in MCL and could be pathogenic for the aggressive presentation of our patient and thus could be further investigated with in vitro and animal models.

Rare Richter Transformation of Chronic Lymphocytic Lymphoma to Hodgkin Lymphoma.

BACKGROUND Richter transformation (RT) is an uncommon clinicopathological condition referring to the development of aggressive lymphoma from chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL) and characterized by sudden clinical deterioration with marked multifocal lymphadenopathy. Transformation of CLL/SLL to diffuse large B-cell lymphoma is the most common (2-9%), but T-cell and Hodgkin transformation (HL) (0.4%) occur, although less frequently. CASE REPORT A 68-year-old woman initially diagnosed with CLL/SLL presented to the hospital with fever, weakness, abdominal pain, and vomiting. The physical examination showed hepatosplenomegaly and extensive abdominal lymphadenopathy on radiological imaging. The laboratory work-up revealed pancytopenia and a markedly increased alkaline phosphatase. In the setting of extensive granulomatous hepatitis, the development of aggressive Hodgkin lymphoma Richter transformation with multi-organ involvement within a few months led to the patient's sudden death. Autopsy findings led to the post-mortem diagnosis of Richter's transformation of CLL. CONCLUSIONS Here, we describe a rare case of Hodgkin lymphoma RT from progressive CLL, with transformation occurring at approximately 12 years after initial diagnosis, despite treatment. Our case report underscores the diagnostic challenges and pitfalls associated with the granulomatous presentation masking RT transformation of CLL to Hodgkin lymphoma. The purpose of this report is to raise suspicion for the clinicopathological signs of Richter transformation in the presence of an atypical granulomatous presentation.

Secondary Plasma Cell Leukemia in a Recurrent Multiple Myeloma: Rare Case Scenario.

Plasma cell leukemia (PCL) is an aggressive hematological condition characterized by the presence of plasma cells in the peripheral smear. It presents as de novo or may arise from multiple myeloma (MM), and hence is diagnosed as primary or secondary PCL, respectively. We report a case of 79-year-old patient diagnosed with MM two years prior to the admission to our institution with prior treatment with bortezomib, lenalidomide and dexamethasone (VRD) and daratumumab, pomalidomide and dexamethasone. Morphologic examination and flow cytometry studies performed on the peripheral smear demonstrated 45%-55% small to medium atypical plasma cells showing a kappa restriction and dim CD138 expression on flow cytometry analysis. The patient was started on brentuximab vedotin, etoposide, cytoxan and dexamethasone, which resulted in near complete elimination of the atypical plasma cells from the peripheral smear one week after the completion of two cycles. He received three cycles of brentuximab vedotin with a gradual decrease in serum free light chain. However, he eventually developed lethargy, weakness and seizures. The involvement of the central nervous system (CNS) by MM was confirmed with MRI, flow cytometry and cytology of cerebrospinal fluid. The treatment with whole brain radiation and ibrutinib was initiated. Our case report highlights the rare case of aggressive clinical course of MM leading to the development of plasmacytoma of kidney, secondary PCL and eventually spreading to the CNS.

Metastatic Ovarian Clear Cell Carcinoma in the Context of In Vitro Fertilization Pregnancy.

Adnexal masses are routinely encountered in the clinical practice. However, adnexal masses during pregnancy are incidental findings and usually resolve spontaneously or can be managed conservatively during pregnancy due to their benign nature. Ovarian malignancy is a rare event to occur during pregnancy. Only a few cases of ovarian clear cell carcinoma (OCCC), a subtype of epithelial ovarian cancers, have been reported in pregnancy and all of which have undergone cystectomy or pregnancy termination prior to the last trimester of pregnancy. We present a unique case of OCCC in a pregnant 38-year old female of Asian ethnicity with endometriosis and an in vitro fertilization (IVF) pregnancy. The OCCC, initially suspected to be of benign nature, was removed via emergency cesarean section during delivery in the late preterm period. The Positron Emission Tomography scan performed a few weeks after delivery confirmed metastatic lesions. Our case study not only emphasizes the need for definitive treatment option for endometriosis but also a close surveillance of all masses diagnosed during pregnancy, in particular with a background of other risk factors such as endometriosis and Asian ethnicity. In addition, our study advocates the need for the guidelines for management of such rare cases.

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine.

Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

Malignant transformation of inflammatory myofibroblastic tumor of urinary bladder: A rare case scenario.

Inflammatory myofibroblastic tumor (IMT) previously known as inflammatory pseudotumor, plasma cell granuloma, pseudosarcoma, myxoid hamartoma or inflammatory myofibrohistiocytic proliferation is recently recognized by World Health Organization (WHO) as "IMT" and is considered as a rare benign tumor of soft tissues occurring commonly in lung, liver and mesentry and omentum. IMT is mainly identified as a lesion of children and young population. In this report, we describe a rare case of IMT occurring in a 93-year-old female in urinary bladder with initial benign presentation but demonstrating rapid malignant transformation as confirmed with morphology and immunohistochemical (IHC) stains. Our report highlights the importance of close follow for IMT showing malignant transformation along with utility of IHC stains to evaluate the degree of malignant transformation in such cases.

Metastatic Pulmonary Calcification with Coexisting Non-specific Interstitial Pneumonia: A Rare Case Report and Literature Review.

Patients with underlying chronic kidney disease (CKD) often have elevated serum calcium and parathyroid hormones due to compromised kidney function. We present a case of a 63-year-old female non-smoker with a surgical history of three renal transplants (at age 47, 51, and 58) along with thyroidectomy and parathyroidectomy, who came to the emergency department with complaints of a persistent dry cough and shortness of breath for the last two months. The patient had been on immunosuppressive drugs-tacrolimus, prednisolone, and mycophenolic acid-since her first renal transplant as well as on cinacalcet after parathyroidectomy (at age 54). An initial computed tomography (CT) scan demonstrated ground glass opacities in the bilateral upper lobes while bronchoscopy revealed few inflammatory cells without any fungi or bacteria. A repeat CT scan performed five days later due to rapid progression of her clinical symptoms showed worsening of ground glass opacities in the bilateral upper lobes and new nodules in the right middle and lower lung lobes. A wedge lung biopsy revealed metastatic pulmonary calcification (MPC) in the right upper lobe and non-specific interstitial pneumonia (NSIP) in the right lower lobe, confirming the co-existence of two different pathological processes most likely complicating the patient's clinical symptoms. Despite comprehensive medical therapy, the patient's symptoms progressively worsened and she is currently undergoing evaluation for both renal and lung transplants. Our case report not only presents a rare case of MPC coexisting with NSIP but also sheds light on the associated morbidity due to pulmonary symptoms in CKD patients.

Interaction of genetic and environmental factors in a Drosophila parkinsonism model.

Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organism Drosophila is an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms in Drosophila that are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, male Drosophila exhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquat-induced oxidative damage. Drosophila mutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production, Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

Heart Failure: Diagnosis, Management and Utilization.

Despite the advancement in medicine, management of heart failure (HF), which usually presents as a disease syndrome, has been a challenge to healthcare providers. This is reflected by the relatively higher rate of readmissions along with increased mortality and morbidity associated with HF. In this review article, we first provide a general overview of types of HF pathogenesis and diagnostic features of HF including the crucial role of exercise in determining the severity of heart failure, the efficacy of therapeutic strategies and the morbidity/mortality of HF. We then discuss the quality control measures to prevent the growing readmission rates for HF. We also attempt to elucidate published and ongoing clinical trials for HF in an effort to evaluate the standard and novel therapeutic approaches, including stem cell and gene therapies, to reduce the morbidity and mortality. Finally, we discuss the appropriate utilization/documentation and medical coding based on the severity of the HF alone and with minor and major co-morbidities. We consider that this review provides an extensive overview of the HF in terms of disease pathophysiology, management and documentation for the general readers, as well as for the clinicians/physicians/hospitalists.

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents.

Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.