Primary Hepatic EBV-DLBCL Lymphoma in the Setting of COVID-19 Infection.

This case study describes an instance of primary hepatic diffuse large B cell lymphoma (DLBCL) in a patient who had prolonged coronavirus disease 2019 (COVID-19). DLBCL rarely presents as a primary hepatic mass. The 53-year-old man sought emergency care because of fatigue and weight loss. Diagnostic tests showed mildly elevated liver enzymes and imaging pointed to several low-density liver lesions. A liver biopsy paired with immunohistochemical testing verified the DLBCL diagnosis. Notably, the patient had COVID-19 4 months before the liver-related symptoms. The link between COVID-19 and the emergence of solid tumor cancers is unclear, but this case underscores its potential significance and the need for further research. This report stresses the importance of recognizing and documenting instances where COVID-19 might influence the onset of solid tumor cancers, including primary hepatic DLBCL.

Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone.

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots. These tests included quality control tests applied routinely in release of Copaxone lots, as well as additional characterization assays, gene expression studies and a rat toxicity study. Even though the Synthon FOGA was designed to copy and compete with Copaxone, the active substances were found to be similar in only 7 of the tested 14 (50%) methods (similar is defined as within approved specifications or within the inherent microheterogeneity range of tested Copaxone batches, or not showing statistically significant differences). With additional methods applied, consistent compositional differences in attributes of surface charge distribution, molecular size, and spatial arrangement were observed. These marked differences were concordantly observed with higher biological activity of some of the Synthon EU FOGA lots compared with Copaxone lots, including potency and cytotoxicity activities as well as gene expression of pathways that regulate apoptosis, IL-2, and inflammation signaling. These observations raise concerns for immunogenicity differences, particularly in (repeated) substitution settings. Another orthogonal finding demonstrated increased frequency of injection-site local toxicity observations for the Synthon EU FOGA in an in vivo daily dosing rat study, thus warranting further qualification of the link between compositional and functional differences in immunogenicity, and potential impact on long-term efficacy and safety.

Drug repurposing from the perspective of pharmaceutical companies.

Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug research and development, combined with the advent of big data repositories and associated analytical methods, has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecular data, appropriate analytical expertise to enable robust insights, expertise and experimental set-up for validation and clinical development know-how. In this review, we describe some of the main approaches to systematic repurposing and discuss the various players in this field and the need for strategic collaborations to increase the likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug development strategy pursued by pharmaceutical companies. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Effects of pelleting diets without or with distillers' dried grains with solubles on growth performance, carcass characteristics, and gastrointestinal weights of growing-finishing barrows and gilts.

Pigs (192 total) were blocked by age and stratified by initial BW (25.75 ± 2.29 kg) into pens (2 barrows and 2 gilts per pen). Within blocks, pens were randomly allotted to treatments in a 2 × 2 factorial arrangement, with 2 diet forms (meal vs. pellet) and 2 distillers' dried grains with solubles (DDGS) inclusion levels (0 vs. 30%). Pigs were weighed at the beginning of the experiment and at the end of each feeding phase (d 35, 70, and 91) and daily feed allotments were recorded. Pigs were slaughtered at the end of the 91-d experiment, and full gastrointestinal (GI) tract and GI tract component weights were recorded immediately following evisceration. Carcass characteristics and meat quality were determined after a 24-h chill. Overall ADG was increased ( < 0.01) 3.2% when pigs were fed pelleted diets rather than meal diets, but there was no effect ( = 0.46) of DDGS inclusion on overall ADG. Overall ADFI of meal-fed pigs fed 30% DDGS was 4.7% greater ( < 0.01) than that of pigs fed 0% DDGS in meal form, but overall ADFI did not differ ( ≥ 0.19) between DDGS inclusion level in pellet-fed pigs (diet form × DDGS inclusion, < 0.01). When fed meal diets, pigs fed 0% DDGS had 2.7% greater ( = 0.02) overall G:F than pigs fed 30% DDGS; however, there was no difference ( = 0.42) in overall G:F between DDGS inclusion levels in pigs fed pelleted diets (diet form × DDGS inclusion, < 0.03). Pigs fed pelleted diets had 2.9% heavier HCW ( = 0.01), 10.4% greater 10th-rib back fat ( = 0.01), and 1.8 percentage units less estimated lean percentage ( = 0.04) than meal-fed pigs. Full GI tracts of pigs fed pelleted diets were 0.33 percentage units less ( = 0.03) of the ending live weight than that of meal-fed pigs due to decreased ( < 0.01) GI tract contents. Inclusion of DDGS increased ( = 0.03) full GI tract weight, large intestine weight ( < 0.01), and GI tract contents ( = 0.02). Severity of parakeratosis of the pars esophagea was greater ( < 0.01) in pellet-fed pigs than in meal-fed pigs, but the magnitude of the difference was likely not great enough to negatively affect drop credit of stomachs. In conclusion, feeding pelleted diets improved growth performance and increased carcass weight and fatness without causing the development of gastric lesions that would reduce the value of the stomach to packers. Furthermore, inclusion of DDGS in diets reduced HCW and dressing percent and increased GI tract and GI tract contents weight but had no effect on gastric lesion development or LM quality.

Use of genetic technologies to compare medicines.

In order to ensure that patients receive the safest and most effective medicines possible, it is often necessary to compare medicines and assess the extent to which they are similar in their clinical impact. Full clinical trials with appropriate endpoints remain the only method to compare the clinical impact of two medicines with absolute certainty. Other available methods (including physicochemical analysis, genomics, and transcriptomics) can provide partial information about certain aspects of a medicine's biological impact, with possible clinical implications. Especially for biologics and non-biological complex drugs, which are more difficult to characterize by physicochemical means than small molecules, genomics and transciptomic studies can yield valuable insights for physicians, regulators, and drug developers. In this review, we cite and summarize a variety of studies that exemplify the emerging science of applying genomics and transcriptomics technologies to compare medicines. We discuss key aspects of experimental design, conduct of genetic assays, and advanced data analysis, all of which are critical for the successful execution of such studies. Finally, we propose new areas for which such studies can be applied to maximize patient benefit and reduce safety issues.

Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

BACKGROUND: Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS: DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS: Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS: Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.

Using genetics to enable studies on the prevention of Alzheimer's disease.

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk.

Primary myeloid sarcoma masquerading as an obstructing duodenal carcinoma.

Myeloid Sarcoma (MS), a rare extra hematopoietic carcinoma composed of blast cells, is located primarily in extramedullary sites such as skin, soft tissue, lymph nodes, and bone. MS usually presents in the setting of coexisting acute myeloid leukemia (AML) and myeloproliferative disorders. Gastrointestinal involvement (GI) is extremely rare from nonspecific abdominal symptoms to obstruction. Eight cases of myeloid sarcoma involving the duodenum including the current case have been reported, overall mean age being 40 years (range 17-71) and M : F ratio 7 : 1. The prognosis of patients with de novo MS cases has been reported to be better than those who have a coexisting leukemia. MS is a rare extramedullary tumor, which should be considered in the differential diagnosis of a soft tissue mass involving the duodenum, especially if there is a coexisting hematological disorder. De novo cases often progress to AML, and current therapy involves Daunorubicin- and Cytarabine-based chemotherapy. The wide cytogenetic and molecular heterogeneity of MS implies a potential role for more targeted MS therapies, which may offer a curative strategy.

Genomic profiling of interpopulation diversity guides prioritization of candidate-genes for autoimmunity.

Autoimmune diseases seem to have strong genetic attributes, and are affected to some extent by shared susceptibility loci. The latter potentially amount to hundreds of candidate genes (CG), creating the need for a prioritization strategy in genetic association studies. To form such a strategy, 26 autoimmune-related CG were genotyped for a total of 72 single nucleotide polymorphisms (SNPs) in three distinct Israeli ethnic populations: Ashkenazi Jews, Sephardic Jews and Arabs. Four quantitative criteria reflecting population stratification were analyzed: allele frequencies, haplotype frequencies, the Fst statistic for homozygotes distribution and linkage disequilibrium extents. According to the consequent interpopulation genomic diversity profiles, the genes were classified into conserved, intermediate and diversified gene groups. Our results demonstrate a correlation between the biological role of autoimmune-related CG and their interpopulation diversity profiles as classified by the different analyses. Annotation analysis suggests that genes more readily influenced by environmental conditions, such as immunological mediators, are 'population specific'. Conversely, genes showing genetic conservation across all populations are characterized by apoptotic and cleaving functions. We suggest a research strategy by which CG association studies should focus first on likely conserved gene categories, to increase the likelihood of attaining significant results and promote the development of gene-based therapies.

A stable murine-based RD114 retroviral packaging line efficiently transduces human hematopoietic cells.

Several barriers exist to high-efficiency transfer of therapeutic genes into human hematopoietic stem cells (HSCs) using complex oncoretroviral vectors. Human clinical trials to date have used Moloney leukemia virus-based amphotropic and gibbon ape leukemia virus-based envelopes in stable retroviral packaging lines. However, retroviruses pseudotyped with these envelopes have low titers due to the inability to concentrate viral supernatants efficiently by centrifugation without damaging the virus and low transduction efficiencies because of low-level expression of viral target receptors on human HSC. The RD114 envelope from the feline endogenous virus has been shown to transduce human CD34+ cells using transient packaging systems and to be concentrated to high titers by centrifugation. Stable packaging systems have potential advantages over transient systems because greater and more reproducible viral productions can be attained. We have, therefore, constructed and tested a stable RD114-expressing packaging line capable of high-level transduction of human CD34+ cells. Viral particles from this cell line were concentrated up to 100-fold (up to 10(7) viral particles/ml) by ultracentrifugation. Human hematopoietic progenitors from cord blood and sickle cell CD34+ cells were efficiently transduced with a Neo(R)-containing vector after a single exposure to concentrated RD114-pseudotyped virus produced from this cell line. Up to 78% of progenitors from transduced cord blood CD34+ cells and 51% of progenitors from sickle cell CD34+ cells expressed the NeoR gene. We also show transfer of a human beta-globin gene into progenitor cells from CD34+ cells from sickle cell patients with this new RD114 stable packaging system. The results indicate that this packaging line may eventually be useful in human clinical trials of globin gene therapy.

[Root-end filling materials in apicoectomy--a review].

An integral component of apicoectomy procedure is the placement of a root end filling material. In this 20 years literature review we identified at least 19 different materials that have been used as root end filling materials. Unfortunately, the ideal material for this purpose is yet to be found. Amalgam is the most frequently used material in apicoectomy procedure and can lead to satisfying results in many cases. IRM, super EBA and MTA are more suitable materials, and give better results in apicoectomy procedures than Amalgam. IRM and super EBA are both ZOE cements. Super EBA is less cytotoxic than IRM, suggesting that the decreased eugenol in Super EBA allows it to be less irritating. MTA gives better results when tested for leakage and biocompatibility than IRM and Super EBA, and has the ability of induction of hard tissue. A possible disadvantage that prevents MTA from being acceptable as "the ideal root-end filling material" is a long setting time that may lead to dislodgment or deformation from root end preparation. Yet, in most cases MTA serves as the best choice for a root end filling material.

Correction of phenotype in a thalassemia mouse model using a nonmyeloablative marrow transplantation regimen.

Gene therapy, the replacement of normal human beta- or gamma-globin genes into the hematopoietic stem cells of patients with homozygous beta-thalassemia, is a promising therapy for the future. High-level lineage-specific stable globin expression in transduced cells reinfused into patients in an autologous transplantation setting could be curative, if successful. Previous studies have shown high-level donor chimerism in nonmyeloablated non-thalassemic hosts. We have now studied the conditions for stable long-term engraftment of normal cells into a thalassemia mouse model that lead to high-level donor chimerism and correction of the abnormal phenotype. Thalassemic female mice treated with 0 to 300 cGy whole-body irradiation received transplantations of donor cells harvested from wild-type males. Engraftment of male cells was quantitated by Y-chromosome polymerase chain reaction analysis of blood and marrow progenitors, and changes in hemoglobin levels, red cell morphology, and spleen size were measured at various times posttransplantation. High-level stable donor cell engraftment was achieved in mice given 200 cGy and receiving transplants of 2 x 10(7) or more donor cells. The anemia, abnormal peripheral blood smears, and splenomegaly improved in the thalassemic mice that had successful engraftment. These studies demonstrate that stable and successful levels of engraftment of normal cells can correct the thalassemic phenotype without fully myeloablating the host. This animal model should allow us to test the amount of cytoreduction required and the level of engraftment and beta-globin expression needed in autologous transplantation of beta-globin gene-transduced cells to correct the abnormal phenotype in thalassemic mice, and it may be relevant to human clinical trials, as well.

Neurocognitive abilities for a clinically depressed sample versus a matched control group of normal individuals.

Depressed patients have been reported to show deficits in tasks that demand memory, planning/sequencing, speeded responding, and effortful responding. Many studies of depressed patients have used inadequate instrumentation or poor control groups. In this investigation, the cognitive performance of 44 patients diagnosed as clinically depressed was compared with the performance of a control group of normal individuals that closely matched the clinical group on the variables of age, gender, race or ethnic group, and educational attainment. The groups were compared on the tasks that compose the Kaufman Adolescent and Adult Intelligence Test (KAIT), which includes reliable and valid measures of most pertinent areas of purported deficit in depressed patients. Multivariate analyses of variance indicated that the depressed and control groups did not differ significantly on KAIT variables, but the depressed patients did differ significantly from the control group on the delayed versus immediate recall of verbal information.

Validation of two new brief cognitive tests with a WAIS-R short form using a hospitalized depressed sample.

The K-FAST and K-SNAP, two new brief cognitive measures designed for adolescents and adults, were validated against another brief measure--a four-subtest short form of the WAIS-R--using a sample of 20 adult patients hospitalized for depression. Data supported the validity of these two new instruments.

Correlations of scores on the Kaufman short neuropsychological assessment procedure and the Kaufman Adolescent and Adult Intelligence Test for a hospitalized depressed sample.

Scores on the K-SNAP, a new brief cognitive measure designed to assess neuropsychological functioning in adolescents and adults, were correlated with KAIT IQs, a comprehensive test that measures fluid and crystallized intelligence. The sample included 33 adolescent and adult patients hospitalized for depression. The K-SNAP correlated significantly higher with fluid than crystallized intelligence.

Blastocystis hominis in hospital employees.

Several reports have appeared that either support or deny the importance of the protozoan Blastocystis hominis as an intestinal pathogen in humans. In this report, we describe the clinical characteristics of B. hominis and its response to therapy in hospital employees found to have the parasite on routine screening of stools. During the study, 49 patients with B. hominis were identified, and 413 stools were examined from these patients. Twenty-nine patients were asymptomatic (59%), and 20 had symptoms of bloating, flatulence, soft/loose stools, or constipation. Of these 20 patients, 10 had symptoms that correlated with the presence or absence of B. hominis, four had symptoms that were independent of B. homonis, and six had other intestinal parasites that could account for their symptoms. Nineteen percent of patients without treatment had eradication of B. hominis from stool on follow-up examination. Metronidazole did not increase this rate. Iodoquinol treatment eradicated the organism in 41% of patients (p less than 0.05), and resulted in the reduction or eradication of the parasite in 62%, as determined by follow-up examination.

[The course and outcome of chronic hepatitis B in children]. / Techenie i iskhody khronicheskogo gepatita B u detei.

Overall 98 children aged 1 to 14 years suffering from chronic hepatitis B (CHB) were followed up clinically for 1 to 6 years. CHB was diagnosed on the basis of the clinical and laboratory data. In the majority of the children, the diagnosis was verified by the results of a histological study of liver biopsy specimens. Chronic active hepatitis (CAH), was revealed in 27 children, chronic persistent hepatitis (CPH) in 31. CHB was marked by the presence of HBe-antigenemia in 89 patients (90.8%). The studies have demonstrated that CHB associated with HBe-antigenemia runs its course with insignificant clinical manifestations and enzymic exacerbations without jaundice. In the presence of persistent HBs-antigenemia, the natural course of CHB (in CAH and CPH) is characterized by seroconversion (from HBeAg to anti-HBe) with a simultaneous decrease and normalization of aminotransferase activity and a reduction of the pathological process activity in the liver (transformation of CAH to CPH). Seroconversion and clinico-biochemical amelioration supervene at different observation periods (after 1-6 years) and do not depend on the initial activity of hepatitis. As the observation period increases, the rate of anti-HBe appearance in the blood rises, amounting to 90% with the observation period exceeding 5 years. The conclusion is made that CHB patients do not need active drug therapy but require long and permanent observation.

Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome.

Three studies were performed to assess more accurately the prevalence, natural history, and appropriate treatment of acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma involving ocular structures. The first study was a prospective examination of 100 male homosexuals with AIDS-related Kaposi sarcoma for signs of ophthalmic involvement. Of the 20 patients who had ophthalmic lesions, 16 had eyelid lesions and seven had conjunctival lesions. In four patients, the ophthalmic lesion was the first, and initially the only, clinically identified manifestation of Kaposi sarcoma. The second study was a retrospective review of all patients with ophthalmic Kaposi sarcoma examined at one institution over a six-year period to determine its natural history and response to therapy. Most lesions were slowly progressive and responded to systemic drug therapy. Six patients were successfully treated with radiation therapy to prevent complications. The third study was a retrospective review of all patients with AIDS-related ophthalmic Kaposi sarcoma treated with local irradiation by one radiation oncologist. Each of 12 patients showed a response to treatment, and ten had a complete resolution of lesions, but recurrences were common. Side effects included skin erythema in six patients and hair loss in one patient. For local treatment of ophthalmic Kaposi sarcoma, irradiation appears to be safe and effective for palliative therapy.

Acute surgical abdomen and myelofibrosis.

Extramedullary hematopoiesis associated with fibrosis is found frequently in the liver and spleen, but seldom in other organs. Acute abdomen due to extramedullary hematopoiesis has been reported in two patients with intestinal obstruction because of heavy infiltration of the terminal ileum. This report describes the case of a 71-year-old woman with myeloid metaplasia involving the gallbladder mimicking acute cholecystitis. As far as we know, involvement of the gallbladder by extramedullary hematopoiesis has never been reported before.