Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies.

B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling.

Racial and ethnic disparities in social isolation and 11-year dementia risk among older adults in the United States.

Aims: Social isolation has been implicated in the development of cognitive impairment, but research on this association remains limited among racial-ethnic minoritized populations. Our study examined the interplay between social isolation, race-ethnicity and dementia.

Methods: We analyzed 11 years (2011-2021) of National Health and Aging Trends Study (NHATS) data, a prospective nationally representative cohort of U.

Improving accuracy of GPT-3/4 results on biomedical data using a retrieval-augmented language model.

Large language models (LLMs) have made a significant impact on the fields of general artificial intelligence. General purpose LLMs exhibit strong logic and reasoning skills and general world knowledge but can sometimes generate misleading results when prompted on specific subject areas. LLMs trained with domain-specific knowledge can reduce the generation of misleading information (i.

Importin 13-dependent axon diameter growth regulates conduction speeds along myelinated CNS axons.

Axon diameter influences the conduction properties of myelinated axons, both directly, and indirectly through effects on myelin. However, we have limited understanding of mechanisms controlling axon diameter growth in the central nervous system, preventing systematic dissection of how manipulating diameter affects myelination and conduction along individual axons. Here we establish zebrafish to study axon diameter.

Disparities in neighbourhood characteristics and 10-year dementia risk by nativity status.

Aims: Prior research indicates that neighbourhood disadvantage increases dementia risk. There is, however, inconclusive evidence on the relationship between nativity and cognitive impairment. To our knowledge, our study is the first to analyse how nativity and neighbourhood interact to influence dementia risk.

New Targeted Therapy Combination Holds Promise to Untangle Hairy Cell Leukemia.

Hairy cell leukemia (HCL) is an uncommon B-cell neoplasm uniquely characterized by a high prevalence of the mutation, which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. In fact, the point mutation is identified in nearly all cases of HCL; however, it is absent in HCL variant (vHCL) and rare in other B-cell neoplasms. Notably, in contrast to melanoma or other BRAF mutant solid tumors, HCL exhibits very few other mutations, potentially explaining the high response rates observed in patients treated with mutant BRAF-targeted agents, such as vemurafenib.

In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis.

Ideal therapies for regenerative medicine or healthy aging require healthy organ growth and rejuvenation, but no organ-level approach is currently available. Using Mycobacterium leprae (ML) with natural partial cellular reprogramming capacity and its animal host nine-banded armadillos, we present an evolutionarily refined model of adult liver growth and regeneration. In infected armadillos, ML reprogram the entire liver and significantly increase total liver/body weight ratio by increasing healthy liver lobules, including hepatocyte proliferation and proportionate expansion of vasculature, and biliary systems.

DKK1 drives immune suppressive phenotypes in intrahepatic cholangiocarcinoma and can be targeted with anti-DKK1 therapeutic DKN-01.

Background And Aims: Dickkopf-1 (DKK1) is associated with poor prognosis in intrahepatic cholangiocarcinoma (iCCA), but the mechanisms behind this are unclear. Here, we show that DKK1 plays an immune regulatory role in vivo and inhibition reduces tumour growth.

Methods: Various in vivo GEMM mouse models and patient samples were utilized to assess the effects of tumour specific DKK1 overexpression in iCCA.

Targeted Therapies in Cancer: To Be or Not to Be, Selective.

Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types.

Macrophages inhibit and enhance endometriosis depending on their origin.

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes.

Efficacy of ferumoxytol versus sodium ferric gluconate in anemia management in outpatient hemodialysis patients: A prospective cohort study.

Background: Intravenous iron is one of the main therapies for anemia management in hemodialysis-dependent patients. Data comparing the efficacy of ferumoxytol versus other parenteral iron supplements are scarce. The objective of the study was to compare the efficacy of ferumoxytol with that of sodium ferric gluconate in outpatient hemodialysis patients.

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development.

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed.

Finding Camel-ot: A Holy Grail against pandemic SARS-CoV-2?

Engineered camelid antibody multimers can potently block SARS-CoV-2 viral entry.

Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with approximately four new cases per 100,000 persons per year. Standard treatment for AML consists of induction chemotherapy with remission achieved in 50 to 75% of cases. Unfortunately, most patients will relapse and die from their disease, as 5-y survival is roughly 29%.

Role of nephrology pharmacists in the management of anemia in outpatient dialysis units: A Canadian model .

Introduction: Hemodialysis patients frequently suffer from anemia. Proper utilization of therapies such as iron and erythropoiesis-stimulating agents (ESAs) is crucial to attain symptom management and established hemoglobin targets. The purpose of this study was to evaluate the clinical and financial impact of nephrology-trained pharmacists on anemia management in these patients.

Treatment of recurrent urinary tract infections in anuric hemodialysis patient, do we really need antimicrobial urinary concentration?

Providing care for patients with chronic kidney disease requires considerations that are unique to this population. Several references recommend the treating urinary tract infections with antibiotics that achieve considerable concentrations in urine however this is not applicable in anuric patients undergoing hemodialysis who are unable to excrete antibiotics significantly in urine. We report successful treatment of several episodes of urinary tract infections in hemodialysis patient highlighting the questionable need for antimicrobial urine concentration.

CNV Radar: an improved method for somatic copy number alteration characterization in oncology.

Background: Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies.

Results: Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data.

Mammary Tumor Cells with High Metastatic Potential Are Hypersensitive to Macrophage-Derived HGF.

Metastasis-associated macrophages (MAM) promote persistent growth of breast cancer cells at the metastatic site and are, thus, an attractive therapeutic target to treat breast cancer metastasis, a leading cause of cancer-related death in women. However, the precise mechanisms behind MAM-mediated metastatic tumor outgrowth have not been fully elucidated. Using mouse models of metastatic breast cancer, we showed that MAMs uniquely expressed hepatocyte growth factor (HGF) in metastatic tumors.

Factors predicting vancomycin therapy outcomes in hemodialysis outpatients and the role of the nephrology stewardship pharmacist.

Background: Vancomycin is the default antibiotic to treat methicillin-resistant Staphylococcus aureus (MRSA) in hemodialysis (HD) units. Current guidelines recommend a vancomycin trough range of 15 to 20 mg/L for serious infections. Data regarding the clinical success of these recommendations are scarce in HD patients.