Natriuretic Peptides in Clinical Practice: A Current Review
Deborah J.W. Lee1, Tar-Choon Aw1,2,3*
1Department of Laboratory Medicine, Changi General Hospital, Singapore
2Clinical Senior Lecturer (Medicine), National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore
3Clinical Professor (Pathology), Duke-NUS Graduate School of Medicine, Singapore
Heart failure is a major clinical problem affecting 64 million people worldwide with a 5-year mortality rate of around 50%. Patients present to the emergency department with inability to breathe properly. Heart failure is an important condition not to be missed as accurate and early diagnosis or exclusion is crucial for timely intervention. Conventionally heart failure was regarded as congestion consequent to fluid accumulation. Currently heart failure is viewed as a complex heterogeneous entity encompassing severity (clinical versus sub-clinical), onset (acute versus chronic), vascular compartment involved (intra- versus extra-vascular), besides fluid accumulation (cardiopulmonary versus generalized). There is a myriad of biomarkers that reflect different parts of heart failure pathophysiology. However, only natriuretic peptides remain as the “gold standard” against which other biomarkers are compared. This review provides a current update on the utility of natriuretic peptides in clinical practice. We will provide a brief overview of natriuretic peptides, the assays, their clinical use in heart failure, some caveats for their use (age, chronic kidney disease, obesity, heart failure with preserved ejection fraction) and highlight some emerging applications.DOI: 10.29245/2578-3009/2023/1.1245 View / Download Pdf
Leflunomide Confers Rapid Recovery from COVID-19 and is Coupled with Temporal Immunologic Changes
Ada Alice Dona1,2#, James F Sanchez1#, Joycelynne M Palmer3, Timothy W. Synold4, Flavia Chiuppesi5, Sandra Thomas2, Enrico Caserta1,2, Mahmoud Singer1,2, Theophilus Tandoh1,2, Arnab Chowdhury3, Amrita Krishnan1, Michael Rosenzweig1, Don J Diamond5, Steven Rosen1*, Flavia Pichiorri1,2*, Sanjeet Dadwal6*
1Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
2Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA
3Department of Computational and Quantitative Sciences, Beckman Research Institute, City of Hope, Duarte, CA
4Department of Cancer Biology, City of Hope, Duarte, CA
5Department of Experimental Therapeutics, City of Hope, Duarte, CA
6Department of Medicine, Division of Infectious Disease, City of Hope, Duarte, CA USA
#These authors contributed equally to this work.
Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.
Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.
Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.
Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.DOI: 10.29245/2578-3009/2023/1.1241 View / Download Pdf
Poor Prognosis in HBV-associated Hepatocellular Carcinoma After Successful Viral Suppression: A Case Series Highlighting a Need for a Cure
Salil Chowdhury1, Daniel Garrido2, Dina Halegoua-DeMarzio3, Christopher Roth4, Hie-Won Hann3*
1Thomas Jefferson University Hospital, Department of Internal Medicine, Philadelphia, PA
2Cooper University Hospital, Digestive Health Institute, Camden, NJ
3Thomas Jefferson University Hospital, Division of Gastroenterology and Hepatology, Philadelphia, PA
4Thomas Jefferson University Hospital, Department of Radiology, Philadelphia PA
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with chronic hepatitis B virus (HBV) infection being an important risk factor for HCC. While nucleos(t)ide analog (NA) therapy has succeeded in suppressing HBV replication and decreasing the risk of HCC in patients with HBV infection, there remains a persistent risk of HCC in those patients. Furthermore, previous studies have highlighted worse survival in patients who developed HCC while on successful NA therapy compared to those who developed HCC without previous NA treatment.
We conducted a long-term, retrospective case study in 5 patients observed between 10 and 25 years, to further explore the poor outcomes in patients with HBV-associated HCC with or without previous NA therapy. Our study highlights the aggression and recurrence of HCC in patients with HBV infection, well-suppressed on NA therapy. The results of our observation emphasize the need for early referral for liver transplantation in these select patients.DOI: 10.29245/2578-3009/2023/1.1242 View / Download Pdf
Implementation of Immunometabolism into Curricula, Scientific Societies, and Immunological Routine Diagnostics
Marc Roder1 and Sascha Kahlfuss1,2,3,4*
1Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
2Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
3Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
4 Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany.
The energy metabolism was demonstrated to directly modulate immune cell function and thereby physiological and detrimental immune responses. In addition, the field of immunometabolism is vastly growing. However, yet there remain fundamental scientific questions in the field, which require the organization of national and international networks as well as the implementation of immunometabolism into curricula, scientific societies, and immunological routine diagnostics to hold the promise of personalized medicine to our patients within the next decade.DOI: 10.29245/2578-3009/2022/4.1243 View / Download Pdf
Soluble Complement Receptor 1 Therapeutics
Matthew P. Hardy1*, Tony Rowe1, and Sandra Wymann2
1CSL, Bio21 Institute, Victoria, Australia
2CSL, CSL Biological Research Centre, Bern, Switzerland
Human Complement Receptor 1 (CR1/CD35) is a potent negative regulator of the complement system. Its mechanism of action is through interaction with the complement activation fragments, C3b and C4b to mediate decay acceleration of the C3 and C5 convertase complexes as well as cleavage of both ligands into inactive fragments via cofactor activity. The result is inhibition of the classical, lectin, and alternative complement pathways. This article will focus on recombinant soluble forms of CR1 that have been generated as potential therapeutics for complement-mediated disorders. Specifically, we will review and contrast the in vitro and in vivo properties of: sCR1 (BRL55730/TP10/CDX-1135), the soluble full-length extracellular domain of human CR1; sCR1-sLex (TP20), a glyco-engineered version of sCR1 additionally targeted to activated endothelium; APT070 (Mirococept), a CR1 fragment conjugated to a myristoylated peptide to enhance tissue targeting; and CSL040, a soluble truncated version of the CR1 extracellular domain which exhibits altered potency and pharmacokinetic properties as compared to the parental molecule. The data obtained from studies on the effects of these CR1-based molecules in animal models of disease and their therapeutic applications will also be discussed.DOI: 10.29245/2578-3009/2022/4.1240 View / Download Pdf
Serologic Response of SARS-CoV-2 mRNA-based Vaccines in Patients with Autoimmune Diseases
Kushal Gandhi1#, Nathan Joshua Manales1#, Asley Sanchez1#, Srikanth Mukkera1*, Anusha Ammu1, Janine Klar1, Alex Gibson1, Evangelina Santiago2, Ailena Mulkey2, Jammie Holland2, Maneesh Mannem1, Lakshmi P. Alahari1, and John Garza1,3
1 School of Medicine, Texas Tech University Health Sciences Center (TTUHSC) at the Permian Basin, TX, USA
2 Clinical Research institute at the Permian Basin, Texas Tech University Health Sciences Center – Permian Basin, TX, USA
3 The University of Texas Permian Basin, Odessa, TX, USA
# Authors contributed equally
Background: In the spring of 2021, coronavirus disease 2019 (COVID-19) vaccines were approved and distributed in the United States for the public to combat the COVID-19 pandemic, but their rapid development leaves some questions unanswered. Vaccine efficacy has always been a point of interest for individuals with rheumatological diseases that take immunosuppressants. This study investigates the vaccine efficacy of two COVID-19 mRNA-based vaccines, Moderna and Pfizer, in subjects in West Texas patients with autoimmune diseases.
Materials and Methods: Blood was collected from Texas Tech University employees who received both doses of COVID-19 vaccines within the past nine months. Subjects were separated into either a group with a known history of rheumatic disease (n=18) or those without (n=18). The samples were analyzed for serum immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels using specific enzyme-linked immunoassay kits, and a neutralizing antibody test using a surrogate virus was conducted as well. Results were analyzed using the Mann-Whitney U test (unpaired, two-tailed).
Results: There was no significant difference in serum IgG and IgA levels between the control and rheumatologic disease groups, but there were significant differences in serum IgM levels. All subjects cleared the threshold for the neutralizing antibody test.
Conclusion: The relatively similar serum IgG levels and the 100% detection rate of effective neutralizing antibodies across both groups indicate promising signs of serological response for subjects with autoimmune conditions, but the relatively low serum IgA and IgM levels of the study the group warrants further investigation.DOI: 10.29245/2578-3009/2022/3.1235 View / Download Pdf
An Acute Inflammation with Special Expression of CD11 & CD4 Produces Abscopal Effect by Intratumoral Injection Chemotherapy Drug with Hapten in Animal Model
Baofa Yu, MD1,2,3,4*, Qiang Fu, MS3, Yan Han, MS3, Jian Zhang3, Dong Chen，MD3
1Immuno Oncology Systems, Inc., San Diego, CA 92122, USA
2TaiMei Baofa Cancer hospital, Dongping, Shandong Province, China, 271500
3Jinan Baofa Cancer hospital, Jinan, Shandong Province, China，250000
4Beijing Baofa Cancer Hospital, Beijing, China
Aim: To study the immunity reaction in tumor by intratumoral injection with a drug PYM and DNP, where it produces abscopal effect by the expression of immunological genes of tumor on home side (left side) while it brings a similar expression of same genes in tumor on opposite side (right side) of mice.
Method: Prepare each tumor on left side of 6 mice and injected intratumoral with a PYM+DNP and PYM control on day 1 and 7. Two day later of day 1, one of groups mice were inoculated with 0.2ml of H22 cells (105/ml) again on the right underarms as opposite side for controls. On day15, the tumor on bilateral sides were excised for qPCR measurement.
Result: It showed that inflammation with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFaÂ in different groups; The inflammation in both side of tumor but these is not only a increasing expression of Collal, CD4, IL12aÂ, TGFb1Â, Elastin, NFKB, Cox2, CD11c, CD8 and TNFaÂ in tumor on home side of mice treated with PYM+DNP but also a similar an increasing expression of same genes in tumor on opposite side of mice which not treated at all. In the control group, it showed that inflammation without an expression of all factors related above immunity genes in both tumor on home treated with PYM only and opposite side of mice which not treated at all.
Conclusion: It indicated that PYM and hapten of DNP can induce an inflammation with stimulation of immunity reaction with the expression of the CoL1a1, CD4, IL12aÂ, TGFb1Â, Elastin, Elastin, Cox2, CD11b/c, CD8, TNFaÂ, which resulted in an abscopale effect. PYM can induce an inflammation but without expression of immuno genes, therefore, hapten is playing an important role with PYM in the special immunity reaction.DOI: 10.29245/2578-3009/2022/3.1236 View / Download Pdf