Assessment of harm reduction receipt and infectious diseases outcomes in United States Veterans with opioid use disorder and history of injection drug use.

Background: Injection drug use (IDU) may lead to negative health outcomes and increased healthcare utilization. In US Veterans (USV) with opioid use disorder (OUD), there is sparse information about healthcare utilization, harm reduction prescription, and outcomes associated with IDU, including severe injection-related infections (SIRI). We assessed psychosocial factors, clinical outcomes, and harm reduction receipt in a cohort of USV with OUD, specifically focusing on persons who inject drugs (PWID).

Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.

Folate-dependent one-carbon (C1) metabolism encompasses distinct cytosolic and mitochondrial pathways connected by an interchange among serine, glycine, and formate. In both the cytosol and mitochondria, folates exist as polyglutamates, with polyglutamylation catalyzed by folylpolyglutamate synthetase (FPGS), including cytosolic and mitochondrial isoforms. Serine is metabolized by serine hydroxymethyltransferase (SHMT)2 in the mitochondria and generates glycine and C1 units for cellular biosynthesis in the cytosol.

Structural Characterization of 5-Substituted Pyrrolo[3,2-]pyrimidine Antifolate Inhibitors in Complex with Human Serine Hydroxymethyl Transferase 2.

We previously discovered first-in-class multitargeted 5-substituted pyrrolo[3,2-]pyrimidine antifolates that inhibit serine hydroxymethyltransferase 2 (SHMT2), resulting in potent in vitro and in vivo antitumor efficacies. In this report, we present crystallographic structures for SHMT2 in complex with an expanded series of pyrrolo[3,2-]pyrimidine compounds with variations in bridge length (3-5 carbons) and the side chain aromatic ring (phenyl, thiophene, fluorine-substituted phenyl, and thiophene). We evaluated structural features of the inhibitor-SHMT2 complexes and correlations to inhibitor potencies (i.

Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.

Multitargeted agents provide tumor selectivity with reduced drug resistance and dose-limiting toxicities. We previously described the multitargeted 6-substituted pyrrolo[3,2-]pyrimidine antifolate with activity against early- and late-stage pancreatic tumors with limited tumor selectivity. Structure-based design with our human serine hydroxymethyl transferase (SHMT) 2 and glycinamide ribonucleotide formyltransferase (GARFTase) structures, and published X-ray crystal structures of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC), SHMT1, and folate receptor (FR) α and β afforded 11 analogues.

Heart Rate Variability Biofeedback Improves Emotional and Physical Health and Performance: A Systematic Review and Meta Analysis.

We performed a systematic and meta analytic review of heart rate variability biofeedback (HRVB) for various symptoms and human functioning. We analyzed all problems addressed by HRVB and all outcome measures in all studies, whether or not relevant to the studied population, among randomly controlled studies. Targets included various biological and psychological problems and issues with athletic, cognitive, and artistic performance.

Mind-body treatments of irritable bowel syndrome symptoms: An updated meta-analysis.

Irritable bowel syndrome (IBS) is a widespread chronic functional gastrointestinal (GI) disorder having bidirectional comorbidity with psychiatric disorders. This review focuses on psychological treatment of IBS, focusing on symptom severity rather than IBS diagnostic criteria. We chose this dimensional approach in order to assess mind-body effects as an alternative or complement to conventional medical treatment, which focuses on symptom relief.

Cellular Pharmacodynamics of a Novel Pyrrolo[3,2-]pyrimidine Inhibitor Targeting Mitochondrial and Cytosolic One-Carbon Metabolism.

Folate-dependent one-carbon (C1) metabolism is compartmentalized in the mitochondria and cytosol and is a source of critical metabolites for proliferating tumors. Mitochondrial C1 metabolism including serine hydroxymethyltransferase 2 (SHMT2) generates glycine for de novo purine nucleotide and glutathione biosynthesis and is an important source of NADPH, ATP, and formate, which affords C1 units as 10-formyl-tetrahydrofolate and 5,10-methylene-tetrahydrofolate for nucleotide biosynthesis in the cytosol. We previously discovered novel first-in-class multitargeted pyrrolo[3,2-]pyrimidine inhibitors of SHMT2 and de novo purine biosynthesis at glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase with potent in vitro and in vivo antitumor efficacy toward pancreatic adenocarcinoma cells.

Novel Pyrrolo[3,2-]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy.

Folate-dependent one-carbon (C1) metabolism is compartmentalized into the mitochondria and cytosol and supports cell growth through nucleotide and amino acid biosynthesis. Mitochondrial C1 metabolism, including serine hydroxymethyltransferase (SHMT) 2, provides glycine, NAD(P)H, ATP, and C1 units for cytosolic biosynthetic reactions, and is implicated in the oncogenic phenotype across a wide range of cancers. Whereas multitargeted inhibitors of cytosolic C1 metabolism, such as pemetrexed, are used clinically, there are currently no anticancer drugs that specifically target mitochondrial C1 metabolism.

Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection.

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed.

Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents.

The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin).

Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents.

To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.

Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores).

All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics.

The PharmD/MD Dual-Degree Program and Its Potential Value in the Pharmaceutical Industry.

The first dual-degree program combining both the doctor of pharmacy (PharmD) and the doctor of medicine (MD) degrees was designed and launched by Rutgers, The State University of New Jersey, in academic year 2013-2014. This joint effort was led by the Ernest Mario School of Pharmacy (EMSOP) and the Robert Wood Johnson Medical School (RWJMS) to combine expertise in both diagnostic and treatment facets of health care and to prepare graduates for leadership roles in providing and managing comprehensive patient care in a variety of settings. One area of potential value of these skill sets is the drug development industry.

Role of ketamine in acute postoperative pain management: a narrative review.

Objectives: The objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across a wide variety of surgeries.

Design: A literature search was performed using the phrases "ketamine" and "postoperative pain." The authors analyzed the studies that involved testing ketamine's effectiveness at controlling postoperative pain.

Negative emotion impacts memory for verbal discourse in pediatric bipolar disorder.

Objectives: Cognitive and emotional deficits have been documented in youth with pediatric bipolar disorder (PBD); however, to date, a systematic evaluation of comprehension and memory for verbally presented information has not been conducted. The effect of emotion on comprehension and memory for verbally presented material also has not been examined. We examined whether youth with PBD have difficulty recalling the big picture (macrostructure) as well as the story details (microstructure).

A bow-tie genetic architecture for morphogenesis suggested by a genome-wide RNAi screen in Caenorhabditis elegans.

During animal development, cellular morphogenesis plays a fundamental role in determining the shape and function of tissues and organs. Identifying the components that regulate and drive morphogenesis is thus a major goal of developmental biology. The four-celled tip of the Caenorhabditis elegans male tail is a simple but powerful model for studying the mechanism of morphogenesis and its spatiotemporal regulation.