Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced renal tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, ii) Phase 2 rheumatoid arthritis patients (RA; n = 266) dosed with PFE-2, iii) lupus patients on standard-of-care therapies (n = 121), and iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.

Reversible effects on female rat fertility with abrocitinib, a Janus kinase 1 inhibitor.

BACKGROUND: Abrocitinib is a Janus kinase (JAK) 1 selective inhibitor approved for the treatment of atopic dermatitis. Female reproductive tissues were unaffected in general toxicity studies, but an initial female rat fertility study resulted in adverse effects at all doses evaluated. A second rat fertility study was conducted to evaluate lower doses and potential for recovery. METHODS: This second study had 4 groups of 20 females each administered abrocitinib (0, 3, 10, or 70 mg/kg/day) 2 weeks prior to cohabitation through gestation day (GD) 7. In addition, 2 groups of 20 rats (0 or 70 mg/kg/day) were dosed for 3 weeks followed by a 4-week recovery period before mating. All mated females were evaluated on GD 14. RESULTS: No effects were observed at ≤10 mg/kg/day. At 70 mg/kg/day (29x human exposure), decreased pregnancy rate, implantation sites, and viable embryos were observed. All these effects reversed 4 weeks after the last dose. CONCLUSIONS: Based on these data and literature on the potential role of JAK signaling in implantation, we hypothesize that these effects may be related to JAK1 inhibition and, generally, that peri-implantation effects such as these, in the absence of cycling or microscopic changes in nonpregnant female reproductive tissues, are anticipated to be reversible.

Thymic lymphoma detection in RORγ knockout mice using 5-hydroxymethylcytosine profiling of circulating cell-free DNA.

A high incidence of thymic lymphoma has been noted in mice deficient of retinoid-related orphan receptor γ2 (RORγ2), which is required for differentiation of naïve CD4+ T cells into TH17 cells. Using a RORγ homozygous knockout (KO) mouse model of thymic lymphoma, we characterized this tumor progression and investigated the utility of 5-hydroxymethylcytosine (5hmC) signatures as a non-invasive circulating biomarker for early prediction of malignancy. No evidence for malignancy was noted in the wild-type mice, while primary thymic lymphoma with multi-organ metastasis was observed microscopically in 97% of the homozygous RORγ KO mice. The severity of thymic lymphoma was not age-dependent in the KO mice of 2 to 4 months old. Differential enrichment of 5hmC in thymic DNA and plasma cell-free DNA (cfDNA) was compared across different stages of tumor progression. Random forest modeling of plasma cfDNA achieved good predictivity (AUC = 0.74) in distinguishing early non-metastatic thymic lymphoma compared to cancer-free controls, while perfect predictivity was achieved with advanced multi-organ metastatic disease (AUC = 1.00). Lymphoid-specific genes involved in thymocyte selection during T cell development (Themis, Tox) were differentially enriched in both plasma and thymic tissue. This could help in differentiating thymic lymphoma from other tumors commonly detected in rodent carcinogenicity studies used in pharmaceutical drug development to inform human malignancy risk. Overall, these results provide a proof-of-concept for using circulating cfDNA profiles in rodent carcinogenicity studies for early risk assessment of novel pharmaceutical targets.

Animal models of inflammatory bowel disease: novel experiments for revealing pathogenesis of colitis, fibrosis, and colitis-associated colon cancer.

Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a lifelong disease that manifests with chronic intestinal inflammation, sequential fibrosis, and an increased risk of colitis-associated colon cancer (CAC). The combined effects of genetic, immunological, environmental, and microbial factors render it difficult to determine the specific mechanism underlying the induction and perpetuation of IBD. Various animal models of IBD have contributed enormously to the understanding of IBD pathogenesis in terms of genomics, transcriptomics, proteomics, microbiome, and drug development of novel therapeutics. Although comprehensive research on IBD has been enabled by advanced technologies, such as genetically engineered models, there is a great need to develop relevant in vivo models of colitis and fibrosis. Here, we review 4 categories of animal models of acute and chronic intestinal inflammation, fibrosis, and CAC: chemically induced, genetically engineered, T cell transfer, and spontaneous gene mutation models.

Pathophysiology and human cancer risk assessment of pharmaceutical-induced thymoma in carcinogenicity studies.

Thymoma, a tumor of thymic lymphocytes or thymic epithelial cells (TECs), is a common spontaneous tumor in Wistar Han rats, especially in females with up to 18% incidence in controls. In addition to sex, there are rat strain differences in background incidence of thymomas such as Sprague Dawley versus Wistar Han rats. Human thymomas are very rare and without clear differences in incidence between males and females. Immunomodulatory and anti-inflammatory pharmaceutical drug classes, including Janus kinase inhibitors, increase the incidence of benign thymoma in two-year rat carcinogenicity studies. Potential non-genotoxic mechanisms that might contribute to the pathogenesis of thymoma development in one sex (female) Wistar Han rats include: (1) hormonal differences, (2) high proliferation rate of TECs, (3) delayed physiologic thymic involution, and/or (4) significant level of immunosuppression at high doses of a pharmaceutical drug. Factors to consider in the human cancer risk assessment of pharmaceutical-induced thymoma are: the genotoxicity of the test article, sex and strain of rats, exposure safety margins, and pathophysiologic differences and similarities of thymoma between rats and humans. Totality of weight of evidence approach and available data suggest thymomas observed in carcinogenicity studies of pharmaceutical drugs are not relevant for human risk at clinically relevant therapeutic doses.

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate.

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 - dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.

A Rare Case of Systemic Lupus Erythematosus With Diffuse Alveolar Hemorrhage and Guillain-Barre Syndrome.

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease with many organ involvements with high morbidity and mortality percentage. It's unusual for systemic lupus erythematosus (SLE) to present with diffuse alveolar hemorrhage (DAH) as the earliest presentation. Diffuse alveolar hemorrhage (DAH) refers to the effusion of blood into the alveoli due to damaged pulmonary microvasculature. It's a rare but severe complication of systemic lupus associated with a high mortality rate. It occurs in three different overlapping phenotypes, which are acute capillaritis, bland pulmonary hemorrhage, and diffuse alveolar damage. diffuse alveolar hemorrhage develops in a short period of time (hours to days). Central and peripheral nervous system complications generally develop during the course of the illness and actually uncommonly from the beginning of the illness. Guillain-Barre syndrome (GBS) is a rare autoimmune polyneuropathy usually occurring post-viral, post-vaccination, or surgery. Systemic lupus erythematosus (SLE) has been associated with several neuropsychiatric manifestations and the development of GBS. GBS as the first presentation of SLE is exceedingly rare. Here, we present the case of a patient with diffuse alveolar hemorrhage and Guillain-Barre syndrome as an atypical presentation of systemic lupus erythematosus (SLE) flare.

Animal models of inflammatory bowel disease: novel experiments for revealing pathogenesis of colitis, fibrosis, and colitis-associated colon cancer

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a lifelong disease that manifests with chronic intestinal inflammation, sequential fibrosis, and an increased risk of colitis-associated colon cancer (CAC). The combined effects of genetic, immunological, environmental, and microbial factors render it difficult to determine the specific mechanism underlying the induction and perpetuation of IBD. Various animal models of IBD have contributed enormously to the understanding of IBD pathogenesis in terms of genomics, transcriptomics, proteomics, microbiome, and drug development of novel therapeutics. Although comprehensive research on IBD has been enabled by advanced technologies, such as genetically engineered models, there is a great need to develop relevant in vivo models of colitis and fibrosis. Here, we review 4 categories of animal models of acute and chronic intestinal inflammation, fibrosis, and CAC: chemically induced, genetically engineered, T cell transfer, and spontaneous gene mutation models.

Leveraging elasticity of blood stenosis to detect the role of a non-Newtonian flow midst an arterial tube: Mazumdar and Keller models.

Blood stenosis is considered one of the most serious risks which face humanity nowadays. In addition, it is also one of the most apparent symptoms of COVID (19) (Corona Virus). Consequently, this research is shedding light on studying the blood flow in case of having blood clots and artery elasticity in the presence of stenosis during studying the flow. Hematopoiesis requires a model of the yield stress fluid, and among the available yield stress fluid models for blood flow, the Herschel-Bulkley model is preferred (because Bingham, Power-law and Newtonian models are its special cases). Navier stokes equation is used to simulate this subject in a mathematical way. The elasticity on the stenosis arterial walls is simulated by Rubinow & Keller model [24] and Mazumdar model [25]. The results reveal exciting behaviors that, in turn, require adequate study of non-Newtonian fluid flow phenomena, especially the results showed that the increase in the parameters related to the elasticity of the walls facilitating the flow of blood through the stenosis area. In addition, a comparison between two elasticity models (Rubinow & Keller model and Mazumdar model) is considered. Further, for normal artery without stenosis, our results are the same as those obtained by Vajravelu et.al [22].

Prevalence of Vitamin D Deficiency among Hemodialysis Patients in Palestine: A Cross-Sectional Study.

INTRODUCTION: The level of vitamin D status and its relationship to kidney function and liver function among patients with and without type 2 diabetes were not studied among Palestinian hemodialysis patients before. The aim of this study was to assess the status of vitamin D in hemodialysis patients with and without type 2 diabetes and its determinants. METHODS: Data were collected on 163 patients on hemodialysis therapy in the Nephrology Department at Najah National University Hospital. Information on age, sex, plasma 25 (OH)D, serum calcium, serum phosphate, parathyroid hormone, dialysis period, hypertension, diabetes, ALT, AST, albumin, alkaline phosphates, and BMI was obtained from the medical records. Data were analyzed using SPSS. Findings. The mean level of 25 (OH)D was 17.3 ± 10.5 ng/ml. Only 12.9% of subjects had 25 (OH)D levels >30 ng/ml, whereas 65% had levels between 10 and 30 ng/ml; the remaining 22.1% were severely vitamin D deficient (<10 ng/ml). Vitamin D deficiency was more prevalent among females. It was not related to PTH, calcium, kidney, or liver function tests. CONCLUSION: Vitamin D deficiency is highly prevalent among patients on hemodialysis with or without DM2.

Electro-magnetically modulated self-propulsion of swimming sperms via cervical canal.

The purpose of this study is to theoretically investigate the electro-magneto-biomechanics of the swimming of sperms through cervical canal in the female reproductive system. During sexual intercourse, millions of sperms migrate into the cervix in large groups, hence we can approximately model their movement activity by a swimming sheet through the electrically-conducting biofluid. The Eyring-Powell fluid model is considered as the base fluid to simulate male's semen with self-propulsive sperms. An external magnetic field is applied on the flow in transverse direction. The governing partial differential system of equations is analytically solved. Creeping flow regimen is employed throughout the channel due to self-propulsion of swimmers along with long wavelength approximation. Solutions for the stream function, velocity profile, and pressure gradient (above and below the swimming sheet) are obtained and plotted with the pertinent parameters. The prominent features of pumping characteristics are also investigated. Results indicate that the propulsive velocity is reduced with an increase in the electric field which is an important feature that can be used in controlling the transport of spermatozoa inside the cervical canal. Not only is the present analysis valid for living micro-organisms, but also valid for artificially designed electro-magnetic micro-swimmers which is further utilized in electro-magnetic therapy taking place in female's lubricous cervical canal filled with mucus.

eRegCom-Quality Improvement Dashboard for healthcare providers and Targeted Client Communication to pregnant women using data from an electronic health registry to improve attendance and quality of antenatal care: study protocol for a multi-arm cluster randomized trial.

BACKGROUND: This trial evaluates interventions that utilize data entered at point-of-care in the Palestinian maternal and child eRegistry to generate Quality Improvement Dashboards (QID) for healthcare providers and Targeted Client Communication (TCC) via short message service (SMS) to clients. The aim is to assess the effectiveness of the automated communication strategies from the eRegistry on improving attendance and quality of care for pregnant women. METHODS: This four-arm cluster randomized controlled trial will be conducted in the West Bank and the Gaza Strip, Palestine, and includes 138 clusters (primary healthcare clinics) enrolling from 45 to 3000 pregnancies per year. The intervention tools are the QID and the TCC via SMS, automated from the eRegistry built on the District Health Information Software 2 (DHIS2) Tracker. The primary outcomes are appropriate screening and management of anemia, hypertension, and diabetes during pregnancy and timely attendance to antenatal care. Primary analysis, at the individual level taking the design effect of the clustering into account, will be done as intention-to-treat. DISCUSSION: This trial, embedded in the implementation of the eRegistry in Palestine, will inform the use of digital health interventions as a health systems strengthening approach. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN10520687 . Registered on 18 October 2018.

Residual time of sinusoidal metachronal ciliary flow of non-Newtonian fluid through ciliated walls: fertilization and implantation.

The monitoring of the ciliated walls in the uterine tube has supreme importance in enhancing the sperm to reach the egg (capacitation processes), and at peristaltic ciliary flow has a more favorable residual time along the canal when compared to the peristaltic flow. Based on the importance of this study, a mathematical simulation of this process has been carried out by studying the behavior of a non-Newtonian magnetized fluid with a Darcy flow model with an oscillating wall having an internal ciliated surface. The governing equation is formed with Eyring-Powell fluid (tubal fallopian fluid) without using any approximations and solved using the Adomian analysis method. Using the vorticity formula, the components of the velocity function, pressure gradient, and stream function are obtained. The influence of relevant parameters is explained through diagramming and discussion. We also analyzed the residue time effects on the flow parameters. The results indicate that peristaltic ciliary flow has a more favorable residual time along the canal when compared to peristaltic flow.

Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent ciprofloxacin derivatives.

Development of new derivatives of commercial antibiotics using different organic reagents and testing these derivatives against different microorganisms are the main goals of this article. Thus, the antibiotic ciprofloxacin, CF, was acylated via reaction with ethyl cyanoacetate and ethyl acetoacetate in basic medium to give the cyanoacetylpiprazinyl dihydroquinoline derivative 3, and oxobutanoylpiprazinyl dihydroquinoline derivative 5, respectively. On the other hand, N-alkylated derivatives 8-10, were prepared through the reaction of CF with chloroacetonitrile, chloroacetyl acetone and chloroacetone in the presence of carbonate salt. In basic medium, both 3 and 10 were coupled with benzenediazonium chloride to afford hydrazono derivatives, which were then cyclized to give 4-(dihydropyridazinecarbonyl)piperazinyl-1,4-dihydroquinoline. Furthermore, compounds 3 and 10 were reacted with benylidenemalononitrile to produce 4H-pyan and pyrido[1,2-a]pyrazine derivatives, respectively. Both 3 and 10 were reacted with DMFDMA to give enaminone derivatives. These enaminones were cyclized to aminopyrimidine derivatives by reacting with urea or thiourea. X-ray, elemental analysis and spectral data were used to illustrate and confirm the structures of the isolated compounds. The bioactivities of the novel compounds were investigated against different gram-positive and gram-negative bacteria. In addition, these novel antibiotic derivatives were tested against ciprofloxacin-resistant bacteria isolated from patients aged 65-74 years. This study reveals that most of the modified drugs show high to moderate antibacterial activity. Additionally, these drugs show good effects against ciprofloxacin-resistant bacteria.

Opinion on Immune Tolerance Therapeutic Development.

Immune tolerance is defined by an active state of immune system unresponsiveness to foreign and self-antigens. Loss of immune tolerance to self-antigens and the resulting overexpression of autoantibodies can lead to tissue injury and development of various autoimmune diseases. In drug development, the goal of newly emerging immune tolerance therapies is to treat autoimmune disorders by restoring the immunoregulatory capacity of the immune system. Development of immune tolerance targets is initiated with the establishment of pharmacological efficacy in relevant disease animal models, followed by their stepwise translation to humans. This review discusses the major challenges to developing tolerance inducing pharmaceutical drugs, including the selection of appropriate disease models to establish efficacy, adequate, and acceptable in vitro and in vivo safety assessments, relevant biomarkers of human safety and efficacy, and finally, some regulatory guidelines to successfully develop immune tolerance therapeutics. [Box: see text].

Kidney Transporters and Drug-Induced Injury in Drug Development.

Influx and efflux kidney tubular transporters are major determinants of the disposition of xenobiotics, including pharmaceutical drugs. On the basolateral membrane of proximal tubular cells, there are influx transporters, such as organic cation transporters. On the apical membrane of proximal tubular cells, there are efflux transporters, such as multidrug and toxin extrusion proteins. The secretion process across the apical membrane into the lumen occurs via efflux transporters which plays an important role in serum creatinine (sCr) elimination in urine. The interference of a pharmaceutical drug with transporters can lead to changes in sCr with no alterations in biomarkers or light microscopic evidence indicative of renal injury. Identification of transporters that influence drug disposition, toxicity, and overall nonclinical safety assessment is important in drug discovery and development programs. This mini review describes some key aspects of kidney tubular transporters and drug-induced renal toxicities in safety risk assessment and drug development.

Prevalence of Hypothyroidism among Dialysis Patients in Palestine: A Cross-Sectional Study.

INTRODUCTION: The kidney affects the thyroid gland causing various derangements in its function whenever the kidney is impaired, even with a minor imperfection in its job, and this makes dialysis patients more prone to thyroid disorders with subsequent increase in mortality and morbidity. This study aims to assess the prevalence of thyroid disease (hypo- and hyperthyroidism) among dialysis patients and their associated factors. METHODS: This cross-sectional study was conducted in the dialysis unit of An-Najah National University Hospital. 209 dialysis patients (60% were male, 57.6 ± 14.5 years, mean age) meeting our inclusion criteria were tested for thyrotropin (TSH) and free thyroxine (FT4) in addition to routine laboratory tests. Findings. The prevalence of hypothyroidism was assessed as 16.3% (95% CI = 11.29% to 21.3%), overt hypothyroidism was 9.1%, and subclinical hypothyroidism was 7.2%. Subclinical hyperthyroidism prevalence was 1%, and no overt hyperthyroidism cases were reported. We observed no significant association between thyroid state and age, gender, duration of dialysis, or weight. Discussion. Hypothyroidism (both subclinical and overt type) is commonly seen in dialysis patients, and its symptoms are ordinary complains even in euthyroid dialysis patients, and this warrants screening programs and more studies on the efficacy of thyroid hormone supplements.

Cardio-renal safety of non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic class in clinical medicine. These are sub-divided based on their selectivity for inhibition of cyclooxygenase (COX) isoforms (COX-1 and COX-2) into: (1) non-selective (ns-NSAIDs), and (2) selective NSAIDs (s-NSAIDs) with preferential inhibition of COX-2 isozyme. The safety and pathophysiology of NSAIDs on the renal and cardiovascular systems have continued to evolve over the years following short- and long-term treatment in both preclinical models and humans. This review summarizes major learnings on cardiac and renal complications associated with pharmaceutical inhibition of COX-1 and COX-2 with focus on preclinical to clinical translatability of cardio-renal data.

Kidney Pathophysiology, Toxicology, and Drug-Induced Injury in Drug Development.

Anatomically, the kidneys are paired, bean-shaped (in most mammals), excretory organs that lie in the retroperitoneum. High blood flow to the kidneys, together with high oxygen consumption, makes them more vulnerable to exposure, via the circulation, and subsequent injury related to high concentrations of xenobiotics and chemicals. In preclinical drug development and safety assessment of new investigational drugs, changes in kidney structure and/or function following drug administration in experimental laboratory animals need to be put in context with interspecies differences in kidney functional anatomy, physiology, spontaneous pathologies, and toxicopathological responses to injury. In addition, translation to human relevance to avoid premature drug termination from development is vital. Thus, detection and characterization of kidney toxicity in preclinical species and human relevance will depend on the preclinical safety testing strategy and collective weight-of-evidence approach including new investigational drug mechanism of action (MOA), preclinical and clinical interspecies differences, and MOA relevance to humans. This review describes kidney macroscopic and microscopic functional anatomy, physiology, pathophysiology, toxicology, and drug-induced kidney toxicities in safety risk assessment and drug development.

Quality of Life among Surgical Residents at King Abdulaziz Medical City in Jeddah, Saudi Arabia.

BACKGROUND: Surgical residency program is considered one of the toughest residency programs, which affects quality of life of the residents during training years. To date, no study has evaluated quality of life among residents, especially surgical residents here in Saudi Arabia. AIM: The objective of this study is to evaluate quality of life among surgical residents. METHODS: The study is a cross-sectional study conducted during September 2018 in King Khalid Hospital at King Abdulaziz Medical City (KAMC) Jeddah, Saudi Arabia. The study utilized the Work-Related Quality of Life, WRQoL, scale which measures perceived quality of life covering six domains: General Well-Being (GWB), Home-Work Interface (HWI), Job and Career Satisfaction (JCS), Control at Work (CAW), Working Conditions (WCS) and Stress at Work (SAW), in addition to demographic questions, asking about (age, gender, marital status, resident level, specialty, BMI, smoking, number of days of exercise per week, hours of sleep per day, on-calls per month, clinics per week, operations per week). RESULTS: Of the 99 surgical residents training at KAMC, 73 residents returned the survey with a response rate of 72.8%. The mean age of the residents was 28 ± 2.1 years with the mean BMI of 25 kg/m2. 54.8% were married, and 42.5% were smokers. Half of the residents (50.7%) working in King Abdulaziz Medical City have low work-related quality of life. In comparison between male and female residents' overall Quality of life, there was no significant difference between them (p = 0.363). CONCLUSIONS: Our main study finding is that half of the residents (50.7%) working at KAMC has low work-related quality of life, and there is no significant difference between male and female residents. Further studies are needed to determine the causes and improve the work-related quality of life among surgical residents.