A Diagnostic Dilemma: A Case of Neurosarcoidosis Without Systemic Sarcoidosis.

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology characterized by non-caseating granulomas in involved organs. Approximately 10% of patients with sarcoidosis exhibit central nervous system involvement. However, the occurrence of isolated neurosarcoidosis without concurrent systemic signs is very rare, affecting less than 1% of patients. We report a case of isolated neurosarcoidosis in a previously healthy patient who initially presented with a single episode of seizure and loss of consciousness. Brain MRI showed T2/fluid-attenuated inversion recovery (FLAIR) hyperintense extra-axial soft tissue mass over the left cerebral convexity measuring approximately 14 mm in maximum depth. Excisional biopsy of the brain mass showed chronic non-caseating granulomatous inflammation with epitheloid cells that was consistent with sarcoidosis. Treatment with high dose-steroids led to significant clinical improvement. At a two-year follow-up, there were no signs of systemic disease or recurrence of the meningeal mass. This case emphasizes the rarity of such presentation, diagnostic difficulties, and the importance of high suspicion and timely management to prevent debilitating neurologic complications.

Unlocking the Potential of Kinase Targets in Cancer: Insights from CancerOmicsNet, an AI-Driven Approach to Drug Response Prediction in Cancer.

Deregulated protein kinases are crucial in promoting cancer cell proliferation and driving malignant cell signaling. Although these kinases are essential targets for cancer therapy due to their involvement in cell development and proliferation, only a small part of the human kinome has been targeted by drugs. A comprehensive scoring system is needed to evaluate and prioritize clinically relevant kinases. We recently developed CancerOmicsNet, an artificial intelligence model employing graph-based algorithms to predict the cancer cell response to treatment with kinase inhibitors. The performance of this approach has been evaluated in large-scale benchmarking calculations, followed by the experimental validation of selected predictions against several cancer types. To shed light on the decision-making process of CancerOmicsNet and to better understand the role of each kinase in the model, we employed a customized saliency map with adjustable channel weights. The saliency map, functioning as an explainable AI tool, allows for the analysis of input contributions to the output of a trained deep-learning model and facilitates the identification of essential kinases involved in tumor progression. The comprehensive survey of biomedical literature for essential kinases selected by CancerOmicsNet demonstrated that it could help pinpoint potential druggable targets for further investigation in diverse cancer types.

Malignant Pleural Effusion As the Initial Presentation of Renal Cell Carcinoma: A Case Report and Literature Review.

Renal cell carcinoma is the most common renal neoplasm. Its presentation is often very occult, and it may be discovered incidentally. It may present with the classic symptoms of back pain, flank pain, hematuria, or hypertension. Renal cell carcinoma may also present with malignant pleural effusion at diagnosis; however, it is very rare. In this case report and literature review, we describe a 77-year-old male who was diagnosed with renal cell carcinoma after presenting with a malignant pleural effusion - an extremely rare phenomenon. An analysis of the literature yielded 13 case reports, including ours, where the diagnostic presentation of renal cell carcinoma was a malignant pleural effusion. Our patient presented with left-sided chest pain. Imaging was suggestive of pleural effusion. CT and MRI imaging demonstrated masses in the upper and lower poles of the right kidney suggestive of renal cell carcinoma. CT imaging also showed lung nodules that were suggestive of pulmonary metastases. Biopsy and immunostaining of pleural tissue were positive for clear cell renal cell carcinoma. Therapeutic thoracentesis was performed. Despite this, the patient developed recurrent large-volume pleural effusions requiring drainage and placement of a pleural catheter. Our patient's extremely rare presentation of malignant pleural effusion as the diagnostic presentation of renal cell carcinoma along with recurrent, large-volume effusions requiring drainage has only been reported in the form of case reports in the literature.

A snapshot of lung cancer: where are we now?-a narrative review.

Background and Objective: The global impact of cancer and cancer-related deaths has been a huge challenge and continues to be a setback in the health sector and beyond even in recent times. Cancer is the second leading cause of death globally with lung cancer (LC) being the second most prevalent malignancy and the leading cause of mortality amongst cancers in men and women worldwide. LC still constitutes a major burden despite recent advances in diagnostic and treatment tools. In this article, we review the trends in LC with an emphasis on non-small cell LC. We aimed to identify nuclear and mitochondrial genetic alterations, microbiome dysbiosis, and their significance in non-small cell LC tumorigenesis as well as its relevance in the future management of LCs. Methods: We identified studies for this review by searching the PubMed, Cochrane, Education Resources Information Center (ERIC), and Surveillance, Epidemiology, and End Results (SEER) databases for English-Language articles published from January 1, 2000 through to July 30, 2022, using keywords: lung cancer, non-small cell lung cancer, early detection, treatment, mitochondria, microbiome and epigenetics. Key Content and Findings: This review will highlight the genomic environment, mitochondrial and nuclear alterations that play a role in the etiopathogenesis of LC and its application in the progression as well as management of the disease. We also elaborate on current molecular tumor biomarkers and their therapeutic targets. Conclusions: LC remains the leading cause of cancer-related deaths globally with poor prognosis despite available treatment options and even recent advances in both diagnostic tools and management guidelines. Human nuclear and mitochondrial alterations clearly play a role in tumorigenesis and progressive genomic evolution is crucial in the early carcinogenesis of LC which is strongly influenced by host immune surveillance. It is imperative that more research and clinical trials be undertaken to appreciate an in-depth understanding of LC from the molecular level to facilitate the discovery of more targeted therapy and overall better management of LC.

Malignant Pleural Effusion Due to Uterine Serous Carcinoma: An Unusual Presentation.

Endometrial cancer is the most common cancer of the female genital tract. It can rarely metastasize to the pleura and present as a malignant pleural effusion. Here we present the case of a 61-year-old female with two primary malignancies, breast and endometrium, who presented to us with shortness of breath. Imaging was suggestive of a malignant pleural effusion. Diagnostic and therapeutic thoracentesis were performed that were initially suggestive of a breast source. However, final pleural fluid studies showed endometrial serous carcinoma as the source of the effusion. The patient received pembrolizumab and lenvatinib treatment and continues to be followed up in our clinic.

Breast Cancer Complicated by Cardiac Tamponade in a Patient With Neurofibromatosis Type 1.

Pericardial effusion may occur as a result of malignant pericarditis, which may in turn result in cardiac tamponade. This paper reports on a rare case of cardiac tamponade that occurred in an African American patient with breast cancer and neurofibromatosis. Herein, we present a case of a 38-year-old woman with neurofibromatosis type 1 (NF1) and breast cancer. She presented with sudden shortness of breath and hypotension. Computed tomography of the chest and an echocardiogram confirmed the presence of cardiac tamponade. Symptomatic relief was obtained following an emergency pericardiocentesis. The patient experienced a recurrence of symptomatic pleuro-pericardial effusion, requiring repeat therapeutic pericardiocentesis and thoracocentesis. To eliminate accumulating fluid, an indwelling drain was placed. The clinical condition of the patient, however, continued to deteriorate and she expired a few days after admission. When patients with breast cancer present with dyspnea, clinicians should maintain a high index of suspicion of cardiac tamponade; urgent imaging should be performed to exclude tamponade. Further research is needed to identify the factors that predict cardiac tamponade in breast cancer patients as well as the optimal treatment for the condition. It is also necessary to examine the relationship between a history of neurofibromatosis and cardiac tamponade.

Artificial intelligence to guide precision anticancer therapy with multitargeted kinase inhibitors.

BACKGROUND: Vast amounts of rapidly accumulating biological data related to cancer and a remarkable progress in the field of artificial intelligence (AI) have paved the way for precision oncology. Our recent contribution to this area of research is CancerOmicsNet, an AI-based system to predict the therapeutic effects of multitargeted kinase inhibitors across various cancers. This approach was previously demonstrated to outperform other deep learning methods, graph kernel models, molecular docking, and drug binding pocket matching. METHODS: CancerOmicsNet integrates multiple heterogeneous data by utilizing a deep graph learning model with sophisticated attention propagation mechanisms to extract highly predictive features from cancer-specific networks. The AI-based system was devised to provide more accurate and robust predictions than data-driven therapeutic discovery using gene signature reversion. RESULTS: Selected CancerOmicsNet predictions obtained for "unseen" data are positively validated against the biomedical literature and by live-cell time course inhibition assays performed against breast, pancreatic, and prostate cancer cell lines. Encouragingly, six molecules exhibited dose-dependent antiproliferative activities, with pan-CDK inhibitor JNJ-7706621 and Src inhibitor PP1 being the most potent against the pancreatic cancer cell line Panc 04.03. CONCLUSIONS: CancerOmicsNet is a promising AI-based platform to help guide the development of new approaches in precision oncology involving a variety of tumor types and therapeutics.

Utility of a Recombinant HSV-1 Vaccine Vector for Personalized Cancer Vaccines.

Current approaches to cancer immunotherapy include immune checkpoint inhibitors, cancer vaccines, and adoptive cellular therapy. These therapies have produced significant clinical success for specific cancers, but their efficacy has been limited. Oncolytic virotherapy (OVT) has emerged as a promising immunotherapy for a variety of cancers. Furthermore, the unique characteristics of OVs make them a good choice for delivering tumor peptides/antigens to induce enhanced tumor-specific immune responses. The first oncolytic virus (OV) approved for human use is the attenuated herpes simplex virus type 1 (HSV-1), Talimogene laherparepvec (T-VEC) which has been FDA approved for the treatment of melanoma in humans. In this study, we engineered the recombinant oncolytic HSV-1 (oHSV) VC2-OVA expressing a fragment of ovalbumin (OVA) as a fusion protein with VP26 virion capsid protein. We tested the ability of VC2-OVA to act as a vector capable of stimulating strong, specific antitumor immunity in a syngeneic murine melanoma model. Therapeutic vaccination with VC2-OVA led to a significant reduction in colonization of tumor cells in the lungs of mice intravenously challenged B16cOVA cells. In addition, VC2-OVA induced a potent prophylactic antitumor response and extended survival of mice that were intradermally engrafted with B16cOVA tumors compared with mice immunized with control virus.

BRASH Syndrome Presenting With Idioventricular Escape Rhythm in a Patient With Trifascicular Block.

Bradycardia, renal failure, atrioventricular (AV) nodal disease, shock, and hyperkalemia (BRASH) syndrome is a well-recognized constellation of distinct clinicopathologic entities comprising bradycardia, renal failure, AV nodal disease, shock, and hyperkalemia. Our patient is an 89-year-old female with a past medical history significant for hypertension and diabetes, who was newly started on labetalol and had recent gastroenteritis; she presented to our Emergency Department with bradycardia and shock. Upon presentation, she showed physical signs of volume depletion, and her blood pressure was 50 mmHg systolic and heart rate was 25 beats per minute. The initial electrocardiogram showed an idioventricular rhythm. The laboratory workup revealed hyperkalemia. The patient was given repeated doses of atropine with no significant response. She was resuscitated with isotonic fluids. The patient improved clinically, her blood pressure stabilized, her potassium level, renal function, and heart rate were normalized, and normal sinus rhythm was restored with a narrow QRS complex. A diagnosis of BRASH syndrome was made retrospectively. Overall, the treatment of this syndrome is largely symptomatic. Hemodynamic support with fluid and treatment of hyperkalemia remains the goal of care. The overall prognosis is good if identified early and managed appropriately.

Cardiac Tamponade in Patients With Breast Cancer: A Systematic Review.

Cardiac tamponade is a rare presentation in breast cancer and may be associated with poor prognosis. In this article, we reviewed the characteristics and survival outcomes of patients with breast cancer who developed cardiac tamponade. Three databases (PubMed, EMBASE and SCOPUS) were searched for relevant articles published from 1978 to 2022 and 16 articles were identified comprising 64 cases. The median age of the cases was 52 years. Cardiac tamponade was diagnosed with echocardiogram or computerized tomography of the chest or both in 91.9%, 1.6% and 6.5% of the cases, respectively. Cytology of the pericardial fluid was done in 90.5% of the cases while biopsy in addition to cytology was done in 9.5% of cases. Tamponade was proven to be malignant in 97.4% of the cases. The initial treatment for tamponade was pericardiocentesis. Adjunct therapies ranged from the insertion of a pericardial window, pericardiectomy, radiotherapy and chemotherapy. The median time from the first treatment of breast cancer to the onset of tamponade was 24 months while the median survival following diagnosis of tamponade was 13 months. There was no significant correlation (spearman rank-sum correlation coefficient= 0.35, p = 0.165) between time to tamponade (interval time from the first diagnosis of breast cancer and the onset of cardiac tamponade) and survival. Cardiac tamponade may adversely affect survival in patients with breast cancer. Early diagnosis with echocardiogram and cytology may guide management and expectations. Further observational studies are needed to determine the predictors of cardiac tamponade and optimal treatment in patients with breast cancer.

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment.

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-Derived Mouse Melanoma Model.

Oncolytic virotherapy (OVT) is now understood to be an immunotherapy that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of antitumor immune responses. The only currently FDA-approved oncolytic virotherapy, T-Vec, is a modified type 1 herpes simplex virus (HSV-1). While T-Vec is associated with limited response rates, its modest efficacy supports the continued development of novel OVT viruses. Herein, we test the efficacy of a recombinant HSV-1, VC2, as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations that block its ability to enter neurons via axonal termini. This greatly enhances its safety profile by precluding the ability of the virus to establish latent infection. VC2 has been shown to be a safe, effective vaccine against both HSV-1 and HSV-2 infection in mice, guinea pigs, and nonhuman primates. We found that VC2 slows tumor growth rates and that VC2 treatment significantly enhances survival of tumor-engrafted, VC2-treated mice over control treatments. VC2-treated mice that survived initial tumor engraftment were resistant to a second engraftment as well as colonization of lungs by intravenous introduction of tumor cells. We found that VC2 treatment induced substantial increases in intratumoral T cells and a decrease in immunosuppressive regulatory T cells. This immunity was critically dependent on CD8+ T cells and less dependent on CD4+ T cells. Our data provide significant support for the continued development of VC2 as an OVT for the treatment of human and animal cancers.IMPORTANCE Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. This, in addition to the increased response rates of oncolytic virotherapy in combination with other immunotherapies, suggests that oncolytic viruses possess significant therapeutic potential for the treatment of cancer. As such, it is important to continue to develop novel oncolytic viruses as well as support basic research into their mechanisms of efficacy. Our data demonstrate significant clinical potential for VC2, a novel type 1 oncolytic herpes simplex virus. Additionally, due to the high rates of survival and the dependence on CD8+ T cells for efficacy, our model will enable study of the immunological correlates of protection for VC2 oncolytic virotherapy and oncolytic virotherapy in general. Understanding the mechanisms of efficacious oncolytic virotherapy will inform the rational design of improved oncolytic virotherapies.

In utero tobacco smoke exposure alters lung inflammation, viral clearance, and CD8+ T-cell responses in neonatal mice infected with respiratory syncytial virus.

Maternal smoking during pregnancy and exposure of infants to cigarette smoke are strongly associated with adverse health effects in childhood including higher susceptibility to respiratory viral infections. Human respiratory syncytial virus (HRSV) is the most important cause of lower respiratory tract infection among young infants. Exacerbation of respiratory disease, including HRSV bronchiolitis and higher susceptibility to HRSV infection, is well correlated with previous smoke exposure. The mechanisms of recurrence and susceptibility to viral pathogens after passive smoke exposure are multifactorial and include alteration of the structural and immunologic host defenses. In this work, we used a well-established mouse model of in utero smoke exposure to investigate the effect of in utero smoke exposure in HRSV-induced pathogenesis. Sample analysis indicated that in utero exposure led to increased lung inflammation characterized by an increased influx of neutrophils to the airways of the infected mice and a delayed viral clearance. On the other hand, decreased HRSV-specific CD8+ T-cell response was observed. These findings indicate that cigarette smoke exposure during pregnancy alters HRSV-induced disease as well as several aspects of the neonatal immune responses.

Distinguishing Lipid Subtypes by Amplifying Contrast from J-Coupling.

Previous work has highlighted the complicated and distinctive dynamics that set signal evolution during a train of spin echoes, especially with nonuniform echo spacing applied to complex molecules like fats. The work presented here regards those signal patterns as codes that can be used as a contrast mechanism, capable of distinguishing mixtures of molecules with an imaging sequence, sidestepping many challenges of spectroscopy. For particular arrays of echo spacings, non-monotonic and distinctive signal evolution can be enhanced to improve contrast between target species. This work presents simulations that show how contrast between two molecules: (a) depends on the specific sequence of echo spacing, (b) is directly linked to the presence of J-coupling, and (c) can be relatively insensitive to variations in B0, T2 and B1. Imaging studies with oils demonstrate this phenomenon experimentally and also show that spin echo codes can be used for quantification. Finally, preliminary experiments apply the method to human liver in vivo, verifying that the presence of fat can lead to nonmonotonic codes like those seen in vitro. In summary, nonuniformly spaced echo trains introduce a new approach to molecular imaging of J-coupled species, such as lipids, which may have implications diagnosing metabolic diseases.

Anti-viral immunity in the tumor microenvironment: implications for the rational design of herpes simplex virus type 1 oncolytic virotherapy.

PURPOSE OF REVIEW: The design of novel herpes simplex type I (HSV-1)-derived oncolytic virotherapies is a balancing act between safety, immunogenicity and replicative potential. We have undertaken this review to better understand how these considerations can be incorporated into rational approaches to the design of novel herpesvirus oncolytic virotherapies. RECENT FINDINGS: Several recent papers have demonstrated that enhancing the potential of HSV-1 oncolytic viruses to combat anti-viral mechanisms present in the tumor microenvironment leads to greater efficacy than their parental viruses. SUMMARY: It is not entirely clear how the immunosuppressive tumor microenvironment affects oncolytic viral replication and spread within tumors. Recent work has shown that the manipulation of specific cellular and molecular mechanisms of immunosuppression operating within the tumor microenvironment can enhance the efficacy of oncolytic virotherapy. We anticipate that future work will integrate greater knowledge of immunosuppression in tumor microenvironments with design of oncolytic virotherapies.

Interferon-Mediated Response to Human Metapneumovirus Infection.

Human metapneumovirus (HMPV) is one of the leading causes of respiratory diseases in infants and children worldwide. Although this pathogen infects mainly young children, elderly and immunocompromised people can be also seriously affected. To date, there is no commercial vaccine available against it. Upon HMPV infection, the host innate arm of defense produces interferons (IFNs), which are critical for limiting HMPV replication. In this review, we offer an updated landscape of the HMPV mediated-IFN response in different models as well as some of the defense tactics employed by the virus to circumvent IFN response.

A Systematic Review of the Incidence, Risk Factors and Case Fatality Rates of Invasive Nontyphoidal Salmonella (iNTS) Disease in Africa (1966 to 2014).

This study systematically reviews the literature on the occurrence, incidence and case fatality rate (CFR) of invasive nontyphoidal Salmonella (iNTS) disease in Africa from 1966 to 2014. Data on the burden of iNTS disease in Africa are sparse and generally have not been aggregated, making it difficult to describe the epidemiology that is needed to inform the development and implementation of effective prevention and control policies. This study involved a comprehensive search of PubMed and Embase databases. It documents the geographical spread of iNTS disease over time in Africa, and describes its reported incidence, risk factors and CFR. We found that Nontyphoidal Salmonella (NTS) have been reported as a cause of bacteraemia in 33 out of 54 African countries, spanning the five geographical regions of Africa, and especially in sub-Saharan Africa since 1966. Our review indicates that NTS have been responsible for up to 39% of community acquired blood stream infections in sub-Saharan Africa with an average CFR of 19%. Salmonella Typhimurium and Enteritidis are the major serovars implicated and together have been responsible for 91%% of the cases of iNTS disease, (where serotype was determined), reported in Africa. The study confirms that iNTS disease is more prevalent amongst Human Immunodeficiency Virus (HIV)-infected individuals, infants, and young children with malaria, anaemia and malnutrition. In conclusion, iNTS disease is a substantial cause of community-acquired bacteraemia in Africa. Given the high morbidity and mortality of iNTS disease in Africa, it is important to develop effective prevention and control strategies including vaccination.

Polio elimination in Nigeria: A review.

Nigeria has made tremendous strides towards eliminating polio and has been free of wild polio virus (WPV) for more than a year as of August 2015. However, sustained focus towards getting rid of all types of poliovirus by improving population immunity and enhancing disease surveillance will be needed to ensure it sustains the polio-free status. We reviewed the pertinent literature including published and unpublished, official reports and working documents of the Global Polio Eradication Initiative (GPEI) partners as well as other concerned organizations. The literature were selected based on the following criteria: published in English Language, published after year 2000, relevant content and conformance to the theme of the review and these were sorted accordingly. The challenges facing the Polio Eradication Initiative (PEI) in Nigeria were found to fall into 3 broad categories viz failure to vaccinate, failure of the Oral Polio Vaccine (OPV) and epidemiology of the virus. Failure to vaccinate resulted from insecurity, heterogeneous political support, programmatic limitation in implementation of vaccination campaigns, poor performance of vaccination teams in persistently poor performing Local Government areas and sporadic vaccine refusals in Northern Nigeria. Sub optimal effectiveness of OPV in some settings as well as the rare occurrence of VDPVs associated with OPV type 2 in areas of low immunization coverage were also found to be key issues. Some of the innovations which helped to manage the threats to the PEI include a strong government accountability frame work, change from type 2 containing OPV to bi valent OPVs for supplementary immunization activities (SIA), enhancing environmental surveillance in key states (Sokoto, Kano and Borno) along with an overall improvement in SIA quality. There has been an improvement in coverage of routine immunization and vaccination campaigns, which has resulted in Nigeria being removed from the list of endemic countries following an absence of new cases for an entire year as of September 2015. However, the last mile remains to be crossed and there is need to further improve and sustain the momentum to complete the journey toward polio elimination.