GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease.

In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia/reperfusion (I/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy.

Antibody-drug conjugates: Principles and opportunities.

Antibody-drug conjugates (ADCs) are immunoconjugates that combine the specificity of monoclonal antibodies with a cytotoxic agent. The most appealing aspects of ADCs include their potential additive or synergistic effects of the innate backbone antibody and cytotoxic effects of the payload on tumors without the severe toxic side effects often associated with traditional chemotherapy. Recent advances in identifying new targets with tumor-specific expression, along with improved bioactive payloads and novel linkers, have significantly expanded the scope and optimism for ADCs in cancer therapeutics.

Endari treatment ameliorates sickle cell-related disruption in intestinal barrier functions and is associated with prolonged survival in sickle cell mice.

Background: Endari (L-glutamine) is a conditional amino acid that reduces the frequency of vaso-occlusive crisis (VOC) in sickle cell disease (SCD).

Aim: To investigate whether Endari could ameliorate intestinal barrier function and improve survival outcomes in SCD.

Methods: We treated female Townes SCD mice with Endari and evaluated their intestinal barrier functions by measuring the recovery of orally administered fluorescein isothiocyanate (FITC)-conjugated dextran 4 kDa in serum, and serum intestinal fatty acid binding proteins (iFABP) and lipopolysaccharide (LPS) concentrations by ELISA.

Returning to employment following allogeneic hematopoietic stem cell transplant: A major problem among survivors.

Quality of life (QoL) is an important aspect of cancer survivorship. One of the most acute problems that impact survivors in many aspects of activities of daily living and compromise their QoL is the inability to return to employment following successful cancer therapy. This is most prominent among survivors after allogeneic hematopoietic stem cell transplant (allo-HSCT).

Utilization and outcome disparities in allogeneic hematopoietic stem cell transplant in the United States.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is increasingly being used in the United States (US) and across the world as a curative therapeutic option for patients with certain high-risk hematologic malignancies and non-malignant diseases. However, racial and ethnic disparities in utilization of the procedure and in outcome following transplant remain major problems. Racial and ethnic minority patients are consistently under-represented in the proportion of patients who undergo allo-HSCT in the US.

CRISPR-based precision medicine for hematologic disorders: Advancements, challenges, and prospects.

The development of programmable nucleases to introduce defined alterations in genomic sequences has been a powerful tool for precision medicine. While several nucleases such as zinc-finger nucleases (ZFN), transcriptor activator-like effector nucleases (TALEN), and meganucleases have been explored, the advent of CRISPR/Cas9 technology has revolutionized the field of genome engineering. In addition to disease modeling, the CRISPR/Cas9 technology has contributed to safer and more effective treatment strategies for hematologic diseases and personalized T-cell-based therapies.

Metabolic syndrome is independently associated with improved overall survival to first-line therapy with immune checkpoint inhibitors in non-small cell lung cancer.

Background: Many co-existing medical conditions may affect the outcome in patients treated with immune checkpoint inhibitors for advanced cancer. There is currently not any information on whether metabolic syndrome (MetS) impacts the clinical outcome in patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell line cancer (NSCLC).

Methods: We carried out a single-center retrospective cohort study to determine the effects of MetS on first-line ICI therapy in patients with NSCLC.

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease.

Voxelotor is an allosteric haemoglobin (Hb) modulator that binds covalently and reversibly to Hb alpha chain to facilitate improved Hb-O affinity and arterial oxygen. It, therefore, reduces the susceptibility of erythrocytes carrying Haemoglobin S to sickle. In this study, we have used GBT1118, an analog of voxelotor, to treat male Townes sickle cell disease (SCD) mice to investigate whether the Hb modulator could attenuate the intestinal pathophysiologic changes associated with SCD.

Intestinal barrier functions in hematologic and oncologic diseases.

The intestinal barrier is a complex structure that not only regulates the influx of luminal contents into the systemic circulation but is also involved in immune, microbial, and metabolic homeostasis. Evidence implicating disruption in intestinal barrier functions in the development of many systemic diseases, ranging from non-alcoholic steatohepatitis to autism, or systemic complications of intestinal disorders has increased rapidly in recent years, raising the possibility of the intestinal barrier as a potential target for therapeutic intervention to alter the course and mitigate the complications associated with these diseases. In addition to the disease process being associated with a breach in the intestinal barrier functions, patients with hematologic and oncologic diseases are particularly at high risks for the development of increased intestinal permeability, due to the frequent use of broad-spectrum antibiotics and chemoradiation.

Chronic graft-versus-host disease in pediatric patients: Differences and challenges.

Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults.

Radioimmunoconjugates in the age of modern immuno-oncology.

Immunotherapy was first investigated as a therapeutic option for treating cancer more than a century ago. During this period, it has gone through numerous disappointments when the successes obtained in the laboratory were not matched clinically. However, recent advances in immuno-oncology have provided the impetus to revisit this therapeutic option.

Piperacillin/Tazobactam and Meropenem Use Increases the Risks for Acute Graft Rejection Following First Kidney Transplantation.

Many broad-spectrum antibiotics (BSA) alter the intestinal microbiome that regulates adaptive immune responses. We hypothesized that BSA use before and early after kidney transplant may affect acute graft rejection (AGR). We carried out a retrospective cohort study on all patients who underwent kidney transplants in our institution.

L-glutamine for sickle cell disease: more than reducing redox.

Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD +  + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC.

Genes modulating intestinal permeability and microbial community are dysregulated in sickle cell disease.

Based on previous studies showing abnormalities in the intestinal pathophysiology characterized by disruption in the gut barrier functions, and alteration in the intestinal microbial load and composition, we set out in the study to examine the expression of genes that might be involved in mediating these changes in Townes sickle cell disease (SCD) mice at 6 months old compared to non-SCD control mice. Using qPCR on total RNA isolated from the intestine, we found downregulation of the TJ genes JAM-A, Occludin, and ZO-1 in both the small intestine and colon. E-Cadherin and MUC2 were also downregulated.

Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice.

Understanding of the importance of the normal intestinal microbial community in regulating microbial homeostasis, host metabolism, adaptive immune responses, and gut barrier functions has opened up the possibility of manipulating the microbial composition to modulate the activity of various intestinal and systemic diseases using fecal microbiota transplant (FMT). It is therefore not surprising that use of FMT, especially for treating relapsed/refractory infections (CDI), has increased over the last decade. Due to the complexity associated with and treatment for these diseases, patients with hematologic and oncologic diseases are particularly susceptible to complications related to altered intestinal microbial composition.

l-glutamine, crizanlizumab, voxelotor, and cell-based therapy for adult sickle cell disease: Hype or hope?

For more than two decades, hydroxyurea was the only therapeutic agent approved by the Food and Drug Administration (FDA) for sickle cell disease (SCD). Although curative allogeneic hematopoietic stem cell transplants (allo-HSCT) were also available, only very few patients underwent the procedure due to lack of matched-related donors. However, therapeutic options for SCD patients increased dramatically in the last few years.

Sperm protein 17 targeting for epithelialovarian cancer treatment in the eraof modern immunoengineering.

Due to the vague symptomatology of the disease and a lack of effective screening methods, most patients with epithelial ovarian cancer (EOC) present late in their disease. Despite advances in chemotherapeutic agents, the prognosis of these patients has uniformly been extremely poor. Although cisplatin-based chemotherapy regimens induce responses in most of these patients, the patients invariably experience disease progression or relapses.

Intestinal pathophysiological abnormalities in steady state and after vaso-occlusive crisis in murine sickle cell disease.

We showed in the present study that, not unlike in adult patients with sickle cell disease (SCD), Townes mice exhibit increases in serum intestinal fatty acid binding proteins and lipopolysaccharides (LPS), together with a breach in the intestinal barrier. These abnormalities increased rapidly after the induction of vaso-occlusive crisis (VOC). We also confirmed higher intestinal microbial density in SCD.

Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions.

Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age.

Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events.

Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing.

Allogeneic hematopoietic stem cell transplant for sickle cell disease: The why, who, and what.

Allogeneic hematopoietic stem cell transplants (allo-HSCTs) from matched-related donors (MRDs), mismatched-related donors (MMRDs), and matched-unrelated donors (MUDs) are increasingly being used to treat sickle cell disease (SCD) in both pediatric and adult patients. The overall results have been extremely encouraging, especially if a MRD is available and the transplant being performed before the age of 13. Although there is a general consensus that patients with high-risk SCD, even in adults and irrespective of donor characteristics, should be offered allo-HSCT, the debates on optimal patient selection and timing of transplant have yet to be resolved.

Antibiotics to modify sickle cell disease vaso-occlusive crisis?

Despite the availability of hydroxyurea, the clinical use of the medication among patients with sickle cell disease (SCD) remains low in the United States. Given the high healthcare utilization cost, SCD requires new therapeutic approaches. Recent studies demonstrated bacterial overgrowth and dysbiosis-related intestinal pathophysiological changes in SCD.

Obesity and diabetes mellitus in patients with sickle cell disease.

Obesity and diabetes mellitus are prevalent among the African-American/Black population. They result in multiple chronic conditions that impact the quality and lifespan of the patients. Their occurrence in patients with sickle cell disease (SCD) will increase the risks for multimorbidity in these patients.