stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia.

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine.

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy.

L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL).

The use of carbamazepine to expedite the metabolism of a long-acting aripiprazole injection.

What Is Known And Objective: Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug.

Case Summary: An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer.

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities.

NPC1L1-dependent transport of 27-alkyne cholesterol in intestinal epithelial cells.

Niemann-Pick C1 Like-1 (NPC1L1) mediates the uptake of micellar cholesterol by intestinal epithelial cells and is the molecular target of the cholesterol-lowering drug ezetimibe (EZE). The detailed mechanisms responsible for intracellular shuttling of micellar cholesterol are not fully understood due to the lack of a suitable NPC1L1 substrate that can be traced by fluorescence imaging and biochemical methods. 27-Alkyne cholesterol has been previously shown to serve as a substrate for different cellular processes similar to native cholesterol.

Advancing Health Equity by Avoiding Judgmentalism and Contextualizing Care.

This article examines the care of a Spanish-speaking woman with end-stage renal disease who returns repeatedly to the emergency department with complications related to missing hemodialysis. Her life circumstances suggest that she has been making difficult but rational decisions in an untenable situation, which is then readily resolved with the assistance of her care team. The case illustrates the pernicious effect of judgmentalism on patients from poor and marginalized communities, which exacerbates health inequity and illuminates the ethical importance of contextualizing patients' care.

Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase.

Choline kinase alpha is a 457-residue protein that catalyzes the reaction between ATP and choline to yield ADP and phosphocholine. This metabolic action has been well studied because of choline kinase's link to cancer malignancy and poor patient prognosis. As the myriad of x-ray crystal structures available for this enzyme show, chemotherapeutic drug design has centered on stopping the catalytic activity of choline kinase and reducing the downstream metabolites it produces.

Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.

Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity.

Effects of Upper Limb Loss or Absence and Prosthesis Use on Postural Control of Standing Balance.

Objective: Persons with upper limb loss or absence experience a high prevalence of falls. Although upper limb prostheses help perform upper limb tasks, fall likelihood increases by six times with prosthesis use. The effects of upper limb loss or absence and prosthesis use on postural control are poorly documented.

Engaging patients, clinicians, and the community in a Clinical Data Research Network: Lessons learned from the CAPriCORN CDRN.

Engaging patients, clinicians, and community members in the development of a research network creates opportunities and challenges beyond engagement in discrete learning activities. This paper describes our experiences establishing and maintaining a stakeholder engagement infrastructure for the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN) and highlights important lessons learned over the first 4 years. During this time, the CAPriCORN Patient and Community Advisory Committee (PCAC) appointed patient, clinician, and community representatives to governance and advisory groups throughout the network, developed a process and criteria for patient- and clinician-centered review of research proposals, and evolved from a large, diverse group to a smaller yet still diverse, more actively engaged group with connections to the broader community.

Identifying small molecule probes of ENTPD5 through high throughput screening.

Ectonucleoside Triphosphate Diphosphohydrolase 5 (ENTPD5) has been shown to be important in maintaining cellular function in cancer, and its expression is upregulated through multiple, unique pathways in certain cancers, including laryngeal, glioblastoma multiforme, breast, testicular, and prostate. ENTPD5 supports cancer growth by promoting the import of UDP-glucose, a metabolite used for protein glycosylation and hence proper glycoprotein folding, into the ER by providing the counter molecule, UMP, to the ER antiporter. Despite its cancer-supporting function, no small molecule inhibitors of ENTPD5 are commercially available, and few studies have been performed in tissue culture to understand the effects of chemical inhibition of ENTPD5.

Role of phospholipase D in bleomycin-induced mitochondrial reactive oxygen species generation, mitochondrial DNA damage, and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a pernicious lung disease characterized by alveolar epithelial apoptosis, dysregulated repair of epithelial injury, scar formation, and respiratory failure. In this study, we identified phospholipase D (PLD)-generated phosphatidic acid (PA) signaling in the development of pulmonary fibrosis (PF). Of the PLD isoenzymes, the protein expression of PLD2, but not PLD1, was upregulated in lung tissues from IPF patients and bleomycin challenged mice.

Four Communication Skills from Psychiatry Useful in Palliative Care and How to Teach Them.

Palliative care and psychiatry share a number of the same priorities, including careful attention to communication skill development. In this article, we identify 4 communication skills helpful in both fields: (1) attending to countertransference, (2) practicing active listening and active reflection, (3) remaining silent and neutral, and (4) naming the emotion. We then describe strategies for teaching these skills.

Identification of a Unique Inhibitor-Binding Site on Choline Kinase α.

Choline kinase α (ChoKα) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKα, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear.

A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias .

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity.

Discovery of human-like L-asparaginases with potential clinical use by directed evolution.

L-asparaginase is a chemotherapy drug used to treat acute lymphoblastic leukemia (ALL). The main prerequisite for clinical efficacy of L-asparaginases is micromolar K for asparagine to allow for complete depletion of this amino acid in the blood. Since currently approved L-asparaginases are of bacterial origin, immunogenicity is a challenge, which would be mitigated by a human enzyme.

T1R3 homomeric sweet taste receptor regulates adipogenesis through Gαs-mediated microtubules disassembly and Rho activation in 3T3-L1 cells.

We previously reported that 3T3-L1 cells express a functional sweet taste receptor possibly as a T1R3 homomer that is coupled to Gs and negatively regulates adipogenesis by a Gαs-mediated but cAMP-independent mechanism. Here, we show that stimulation of this receptor with sucralose or saccharin induced disassembly of the microtubules in 3T3-L1 preadipocytes, which was attenuated by overexpression of the dominant-negative mutant of Gαs (Gαs-G226A). In contrast, overexpression of the constitutively active mutant of Gαs (Gαs-Q227L) as well as treatment with cholera toxin or isoproterenol but not with forskolin caused disassembly of the microtubules.

The differential ability of asparagine and glutamine in promoting the closed/active enzyme conformation rationalizes the Wolinella succinogenes L-asparaginase substrate specificity.

Many side effects of current FDA-approved L-asparaginases have been related to their secondary L-glutaminase activity. The Wolinella succinogenes L-asparaginase (WoA) has been reported to be L-glutaminase free, suggesting it would have fewer side effects. Unexpectedly, the WoA variant with a proline at position 121 (WoA-P) was found to have L-glutaminase activity in contrast to Uniprot entry P50286 (WoA-S) that has a serine residue at this position.

Targeted Delivery of Deoxycytidine Kinase to Her2-Positive Cells Enhances the Efficacy of the Nucleoside Analog Fludarabine.

Cytotoxic drugs, such as nucleoside analogs and toxins, commonly suffer from off-target effects. One approach to mitigate this problem is to deliver the cytotoxic drug selectively to the intended site. While for toxins this can be achieved by conjugating the cell-killing moiety to a targeting moiety, it is not an option for nucleoside analogs, which rely on intracellular enzymes to convert them to their active triphosphorylated form.

Structural Insight into Substrate Selectivity of Erwinia chrysanthemi L-asparaginase.

l-Asparaginases of bacterial origin are a mainstay of acute lymphoblastic leukemia treatment. The mechanism of action of these enzyme drugs is associated with their capacity to deplete the amino acid l-asparagine from the blood. However, clinical use of bacterial l-asparaginases is complicated by their dual l-asparaginase and l-glutaminase activities.

Fluoroscopy-free Atrial Transseptal Puncture.

Introduction: Fluoroscopy is traditionally used in atrial transseptal puncture (TSP); however fluoroscopy exposes patient and physician to excess radiation. Here, we describe a feasibility study of a zero-fluoroscopy transseptal puncture (ZFTSP) technique utilising electroanatomical mapping (EAM) and intracardiac echo (ICE) in a small case series of patients undergoing ablation for atrial fibrillation (AF). We then compare this technique to other established ZFTSP techniques for paroxysmal AF ablation.

Domain-specific impairment in cognitive control among remitted youth with a history of major depression.

Aim: Impairment in neuropsychological functioning is common in major depressive disorder (MDD), but it is not clear to what degree these deficits are related to risk (e.g. trait), scar, burden or state effects of MDD.

RBM25/LUC7L3 function in cardiac sodium channel splicing regulation of human heart failure.

Alternative splicing is a posttranscriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases.