Model-Informed Assessment of Probability of Phase 3 Success for Ritlecitinib in Patients with Moderate-to-Severe Ulcerative Colitis.

Ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor, was evaluated in patients with ulcerative colitis (UC) in a phase 2b trial. Model-informed drug development strategies were applied to bridge observations from phase 2b to predictions for a proposed phase 3 study design to assess the probability of achieving the target efficacy outcome. A longitudinal exposure-response model of the time course of the 4 Mayo subscores (rectal bleeding, stool frequency, physician's global assessment, and endoscopic subscore) in patients with UC receiving placebo or ritlecitinib was developed using population modeling approaches and an item response theory framework. The quantitative relationships between the 4 Mayo subscores accommodated the prediction of composite endpoints such as total Mayo score and partial Mayo score (key endpoints from phase 2b), and modified clinical remission and endoscopic remission (proposed phase 3 endpoints). Clinical trial simulations using the final model assessed the probability of candidate ritlecitinib dosing regimens (including those tested in phase 2b and alternative) and phase 3 study designs for achieving target efficacy outcomes benchmarked against an approved treatment for moderate-to-severe UC. The probabilities of achieving target modified clinical remission and endoscopic improvement outcomes at both weeks 8 and 52 for ritlecitinib 100 mg once daily was 74.8%. Model-based assessment mitigated some of the risk associated with proceeding to pivotal phase 3 trials with dosing regimens of which there was limited clinical experience.

VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response.

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the tumor microenvironment. In summary, SNS-101, currently in Phase I clinical trials, emerges as a promising therapeutic biologic for a wide range of patients whose cancer is refractory to current immunotherapy regimens.

Engineering water exchange is a safe and effective method for magnetic resonance imaging in diverse cell types.

Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

A Dual-Gene Reporter-Amplifier Architecture for Enhancing the Sensitivity of Molecular MRI by Water Exchange.

The development of genetic reporters for magnetic resonance imaging (MRI) is essential for investigating biological functions in vivo. However, current MRI reporters have low sensitivity, making it challenging to create significant contrast against the tissue background, especially when only a small fraction of cells express the reporter. To overcome this limitation, we developed an approach for amplifying the sensitivity of molecular MRI by combining a chemogenetic contrast mechanism with a biophysical approach to increase water diffusion through the co-expression of a dual-gene construct comprising an organic anion transporting polypeptide, Oatp1b3, and a water channel, Aqp1. We first show that the expression of Aqp1 amplifies MRI contrast in cultured cells engineered to express Oatp1b3. We demonstrate that the contrast amplification is caused by Aqp1-driven increase in water exchange, which provides the gadolinium ions internalized by Oatp1b3-expressing cells with access to a larger water pool compared with exchange-limited conditions. We further show that our methodology allows cells to be detected using approximately 10-fold lower concentrations of gadolinium than that in the Aqp1-free scenario. Finally, we show that our approach enables the imaging of mixed-cell cultures containing a low fraction of Oatp1b3-labeled cells that are undetectable on the basis of Oatp1b3 expression alone.

Engineering water exchange is a safe and effective method for magnetic resonance imaging in diverse cell types.

Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

Solvothermal synthesis of 3D rod-shaped Ti/Al/Cr nano-oxide for photodegradation of wastewater micropollutants under sunlight: a green way to achieve SDG:6.

Waterbodies are day-by-day polluted by the various colored micropollutants, e.g., azo dyes enriched (carcinogenic, non-biodegradable) colored wastewater from textile industries. Water pollution has become a serious global issue as ~ 25% of health diseases are prompted by pollution as reported by WHO. Around 1 billion people will face water scarcity by 2025 and this water crisis is also a prime focus to the UNs' sustainable development goal 6 (SDG6: clean water and sanitation). To prevent the water pollution caused by micropollutants, a mesoporous, 3D rod-like nano-oxide Ti/Al/Cr (abbreviated as TAC) has been synthesized via the solvothermal method. TAC degraded all classes of azo dyes (mono, di, tri, etc.) with > 90% efficiency under renewable energy source solar irradiation within the pH range 2-11. The detailed study was done on the photodegradation of carcinogenic di-azo dye Congo red (CR) which is banned in many countries. TAC showed 90.64 ± 2% degradation efficiency for CR at pH 7. The proposed photodegradation mechanism of CR was confirmed by the high-resolution liquid chromatography-mass spectroscopy (HRLC-MS) analysis obeying the Pirkanniemi path. The photodegradation obeyed the pseudo-1st-order kinetics and was reusable up to successive 5 cycles which can be an efficient tool to meet the UNs' SDG:6.

Unveiling Potential Targeted Therapeutic Opportunities for Co-Overexpressed Targeting Protein for Xklp2 and Aurora-A Kinase in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most prevalent and leading causes of cancer deaths globally, with limited diagnostic and clinically significant therapeutic targets. Identifying the genes and processes involved in developing and progressing LUAD is crucial for developing effective targeted therapeutics and improving patient outcomes. Therefore, the study aimed to explore the RNA sequencing data of LUAD from The Cancer Genome Atlas (TCGA) and gene expression profile datasets involving GSE10072, GSE31210, and GSE32863 from the Gene Expression Omnibus (GEO) databases. The differential gene expression and the downstream analysis determined clinically significant biomarkers using a network-based approach. These therapeutic targets predominantly enriched the dysregulation of mitotic cell cycle regulation and revealed the co-overexpression of Aurora-A Kinase (AURKA) and Targeting Protein for Xklp2 (TPX2) with high survival risk in LUAD patients. The hydrophobic residues of the AURKA-TPX2 interaction were considered as the target site to block the autophosphorylation of AURKA during the mitotic cell cycle. The tyrosine kinase inhibitor (TKI) dacomitinib demonstrated the strong binding potential to hinder TPX2, shielding the AURKA destabilization. This in silico study lays the foundation for repurposing targeted therapeutic options to impede the Protein-Protein Interactions (PPIs) in LUAD progression and aid in future translational investigations.

Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer.

RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopeptide based non-immunogenic, biocompatible siRNA transporter to facilitate the clinical translation in future. Our designed lipopeptide has an Arginine-Sarcosine-Arginine segment for providing optimum protease-stability, minimizing adjacent arginine-arginine repulsion and reducing intermolecular aggregation and α-tocopherol as the lipidic moiety for facilitating cellular permeabilization. Interestingly, our designed non-immunogenic siRNA transporter has exhibited significantly better long term transfection efficiency than HiPerFect and can transfect hard to transfect primary cell line, HUVEC. Our engineered siRNA therapeutics demonstrated high efficacy in managing metastasis against triple negative breast cancer by disrupting the crosstalk of endothelial cells and MDA-MB-231 and reduced stemness and metastatic markers, as evidenced by downregulating critical oncogenic pathways. Our study aimed at silencing Notch1 signalling to achieve "multi-targeted" therapy with a single putative molecular medicine. We have further developed mechanistically rational combination therapy combining Notch1 silencing with a repurposed drug m-TOR inhibitor, metformin, which demonstrated synergistic interaction and enhanced antitumor efficacy against cancer metastasis.

Engineering ligand stabilized aquaporin reporters for magnetic resonance imaging.

Imaging transgene expression in live tissues requires reporters that are detectable with deeply penetrant modalities, such as magnetic resonance imaging (MRI). Here, we show that LSAqp1, a water channel engineered from aquaporin-1, can be used to create background-free, drug-gated, and multiplex images of gene expression using MRI. LSAqp1 is a fusion protein composed of aquaporin-1 and a degradation tag that is sensitive to a cell-permeable ligand, which allows for dynamic small molecule modulation of MRI signals. LSAqp1 improves specificity for imaging gene expression by allowing reporter signals to be conditionally activated and distinguished from the tissue background by difference imaging. In addition, by engineering destabilized aquaporin-1 variants with different ligand requirements, it is possible to image distinct cell types simultaneously. Finally, we expressed LSAqp1 in a tumor model and showed successful in vivo imaging of gene expression without background activity. LSAqp1 provides a conceptually unique approach to accurately measure gene expression in living organisms by combining the physics of water diffusion and biotechnology tools to control protein stability.

Groundwater quality enumeration and health risk in the extended part of Chhotanagpur granite gneiss complex of India.

The majority of people on the earth bank largely on groundwater to quench their thirst. In the era of rapid population growth, the over-exploitation of groundwater gives rise to water scarcity, and people find themselves in distress to manage safe drinking water. In this backdrop, the present study is carried out in the terrain of Pre-Cambrian igneous and high- to low-graded metamorphic rocks, to assess the groundwater potential zones (GWPZs) and evaluation of groundwater quality. The map of GWPZ is produced employing the multi-criteria decision-making model and geospatial technology. It unveils that around 29% area of the watershed enjoys good GWPZ, whereas around 43% area experiences low GWPZ. The overall accuracy of the simulated model is 92%. The water quality index indicates that 68% of water samples belong to excellent to good water quality. A significant proportion of water samples (24%) are found to be unsuitable for drinking, which may be due to groundwater contamination by the process of leaching of mineral-rich weathered rocks. The presence of fluoride (F-) beyond the maximum permissible limit (1.5 mg L-1) of WHO is recorded among 18% samples of the watershed, where 24,963 souls including 3457 children aged between 0 and 6 years lived and might have ingested F- through drinking water. Hence, the health risk of those people is quite high. Children are at a more non-carcinogenic health risk of F- than adults. The study also confirms no statistically significant difference (p ˃ 0.05) is observed between low and high GWPZ with respect to groundwater quality. The study recommends adopting a sustainable outlook to explore GWPZ, and an assessment of drinking water quality must be done before drinking.

Identification of therapeutic miRNAs from the arsenic induced gene expression profile of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with a rising worldwide burden due to a lack of efficient treatment techniques and diagnosis after it has metastasized. Therefore, small non-coding RNA (miRNAs) as protein translation inhibitors are gaining attention that degrades or suppress specific gene transcripts, making it a prime strategy for oncogenes or tumor suppression. Systematic research with miRNAs in combination with Arsenic, which has been employed as a drug to treat several diseases, including cancer, was focused on cellular responses through interacting with multiple biological targets. The differential gene expression of the DNA microarray dataset (GSE48441) revealed the association of sterol, cholesterol, and lipid metabolic processes. With the aid of the network pharmacology approach, hsa-mir-335-5p was uncovered to negatively regulate the important nodes driving the transport and utilization of essential compounds for the rapid growth and proliferation of cancer cells. The binding energies of the duplexes were validated by the minimal free energies of the mRNAs for hsa-mir-335-5p, indicating energetically desirable binding association. The molecular interactions between hsa-mir-335-5p, which interacts with the Argonaute protein in the RNA induced silencing complex, and the target-specific genes were also investigated, revealing its susceptibility to be employed in in vitro studies.

Preoperative risk factors associated with peri-operative psychiatric diagnosis in oral cancer patients.

Background: Head and neck cancers (HNCs) are one of the commonest cancers in low- and middle-income countries. There is a paucity of data on comorbid psychiatric problems associated with HNCs. The present study is aimed at reporting the pattern of psychiatric caseness in HNC patients who were referred to specialist psycho-oncology service and also investigate the predictors of psychiatric caseness in oral cancer patients. Methods: Case records of all patients with HNC referred to an integrated psycho-oncology service over 7 years (October 2011-December 2018) from a cancer hospital were analysed. All patients were assessed by a trained consultant psychiatrist and ICD-10 diagnoses were ascertained based on a clinical interview with the patients and family members. Associations of psychiatric caseness for consecutive oral cancer patients assessed by the psycho-oncology services over 2 years (January 2017-December 2018) were calculated by using univariate and multivariate statistical methods. Simple descriptive statistics of the referred patients were conducted, followed by logistic regression to find the associations of psychiatric caseness in oral cancer patients. Results: The psycho-oncology service assessed 771 HNC patients over 7 years. The commonest referrals were patients with oral cancer (75%, 558/771). For the years 2017-2018, 179 consecutive oral cancer patients were evaluated by the psycho-oncology service. Multivariate logistic regression analysis showed that being a woman (OR = 2.33; 95% CI = 1.02-5.32; p = 0.04); having worries about having pain in the post-operative period (OR = 2.55; 95% CI = 1.2-5.38; p = 0.01); worries about implications of the cancer and its treatment on the family (OR = 3.5; 95% CI = 1.19-10.57; p = 0.02); and longer duration of hospital stay period (OR = 1.08; 95% CI = 1.003-1.16; p = 0.04) were independently associated with psychiatric caseness even after controlling for confounders. Discussion: Specialist psycho-oncology services are important in the management of oral cancer patients and in addressing the mental health needs of this very vulnerable group of patients. A combination of psychoeducation, pragmatic psychological interventions and medications were used to treat these patients.

Electrostatically Directed Long-Range Self-Assembly of Nucleotides with Cationic Nanoparticles To Form Multifunctional Bioplasmonic Networks.

Precise control over interparticle interactions is essential to retain the functions of individual components in a self-assembled superstructure. Here, we report the design of a multifunctional bioplasmonic network via an electrostatically directed self-assembly process involving adenosine 5'-triphosphate (ATP). The present study unveils the ability of ATP to undergo a long-range self-assembly in the presence of cations and gold nanoparticles (AuNP). Modelling and NMR studies gave a qualitative insight into the major interactions driving the bioplasmonic network formation. ATP-Ca2+ coordination helps in regulating the electrostatic interaction, which is crucial in transforming an uncontrolled precipitation into a kinetically controlled aggregation process. Remarkably, ATP and AuNP retained their inherent properties in the multifunctional bioplasmonic network. The generality of electrostatically directed self-assembly process was extended to different nucleotide-nanoparticle systems.

Exposure-Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies.

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E-R models, including induction patients predicted placebo-adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.

Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation.

Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H2S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell's own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfides in vitro as well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H2S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate 1a permeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications.

Protamine-Controlled Reversible DNA Packaging: A Molecular Glue.

Packaging paternal genome into tiny sperm nuclei during spermatogenesis requires 106-fold compaction of DNA, corresponding to a 10-20 times higher compaction than in somatic cells. While such a high level of compaction involves protamine, a small arginine-rich basic protein, the precise mechanism at play is still unclear. Effective pair potential calculations and large-scale molecular dynamics simulations using a simple idealized model incorporating solely electrostatic and steric interactions clearly demonstrate a reversible control on DNA condensates formation by varying the protamine-to-DNA ratio. Microscopic states and condensate structures occurring in semidilute solutions of short DNA fragments are in good agreement with experimental phase diagram and cryoTEM observations. The reversible microscopic mechanisms induced by protamination modulation should provide valuable information to improve a mechanistic understanding of early and intermediate stages of spermatogenesis where an interplay between condensation and liquid-liquid phase separation triggered by protamine expression and post-translational regulation might occur. Moreover, recent vaccines to prevent virus infections and cancers using protamine as a packaging and depackaging agent might be fine-tuned for improved efficiency using a protamination control.

Psycho-oncology service provisions for hospitalised cancer patients before and during the COVID-19 pandemic in an oncology centre in eastern India.

BACKGROUND: Addressing the mental health needs of cancer patients and their caregivers improves the quality of care the patient receives in any cancer care ecosystem. International practice currently encourages integrated care for physical and mental health in oncology. The coronavirus disease (COVID-19) pandemic has affected the delivery of healthcare services across the world. The current research paper is on the psycho-oncology service provision for hospitalised cancer patients before and during the COVID-19 pandemic. METHODS: All patients who were referred to psycho-oncology services during the study period of 1 month, in the two successive years of 2019 and 2020, were included in the study. Retrospective data were collected from the centralised electronic medical records for patients. Data included cancer diagnosis, reason for admission, admitting team and reason for a psychiatric referral. Other parameters that were measured were the timing of the psychiatric assessment, psychiatric diagnosis and psycho-oncology care provided, which included psychological interventions carried out and medications prescribed. The overall institutional data on cancer care provision are also presented in brief to provide context to the psycho-oncology services. RESULTS: Integrated psycho-oncology services reviewed and managed patients round the year in the hospital where the study was conducted. During the 1-month study period, in 2019 and 2020, the total number of hospitalised cancer patients managed by the services was 74 and 52, respectively. During the study period of 2020, 292 patients with cancer who were being treated in the hospital had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tested on reverse transcription-polymerase chain reaction (RT-PCR) and 50 members of healthcare staff also tested positive. The most common diagnosis of patients was found to be stress-related adjustment disorder [16/74 (21.6%) in 2019 and 16/52 (30.8%) in 2020]. The paper discusses the common stressors voiced by the patients and their caregivers during the COVID-19 pandemic. Several challenges of providing psychological services were overcome by the team and the paper touches upon the common strategies that were used during the pandemic. Most patients did not need medications, but a significant minority did benefit from treatment with psychotropic medications. Simple psychological interventions such as sleep hygiene, supportive therapy sessions and psycho-education benefited many patients and were feasible even during the pandemic. CONCLUSION: The provision of psycho-oncology services to cancer patients and their caregivers was important before and during the COVID-19 pandemic.Watch a video which illustrates the psycho-oncology service provisions in an oncology centre in Eastern India during the COVID-19 pandemic here: https://ecancer.org/en/video/9707-psycho-oncology-service-provisions-for-hospitalised-cancer-patients-before-and-during-the-covid19-pandemic.

Structural basis for non-radical catalysis by TsrM, a radical SAM methylase.

Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of L-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5'-deoxyadenosyl 5'-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe-4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion.

Therapeutic Drug Monitoring for Current and Investigational Inflammatory Bowel Disease Treatments.

This article reviews therapeutic drug monitoring (TDM) use for current inflammatory bowel disease (IBD) treatments. IBD comprises Crohn's disease and ulcerative colitis-chronic gastrointestinal inflammatory disorders. Treatment options for moderate to severe IBD include thiopurines; methotrexate; biologic agents targeting tumor necrosis factor, α4ß7 integrin or interleukins 12 and 23; and Janus kinase inhibitors. TDM is recommended to guide treatment decisions for some of these agents. Published literature concerning TDM for IBD treatments was reviewed. S.D.L., R.S., and E.V.L. drew on their clinical experiences. Polymorphisms resulting in altered enzymatic activity inactivating thiopurine metabolites can lead to myelotoxicity and hepatotoxicity. Increased elimination of biologic agents can result from immunogenicity or higher disease activity, leading to low drug concentration and consequent nonresponse or loss of response. TDM may aid treatment and dose decisions for individual patients, based on monitoring metabolite levels for thiopurines, or serum drug trough concentration and antidrug antibody levels for biologic agents. Challenges remain around TDM implementation in IBD, including the lack of uniform assay methods and guidance for interpreting results. The Janus kinase inhibitor tofacitinib is not impacted by enzyme polymorphisms or disease activity, and is not expected to stimulate the formation of neutralizing antidrug antibodies. TDM is associated with implementation challenges, despite the recommendation of its use for guiding many IBD treatments. Newer small molecules with less susceptibility to patient variability factors may fulfill the unmet need of treatment options that do not require TDM, although further study is required to confirm this.