Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30.5% in the United States). Designing cell therapies to target AML is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations. Furthermore, TAAs are also expressed on healthy cells, leading to toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells with a multi-input gene circuit consisting of chimeric antigen receptors (CARs) controlled by OR and NOT logic gates. The OR gate kills a range of AML cells from leukemic stem cells to blasts using a bivalent CAR targeting FLT3 and/or CD33. The NOT gate protects healthy hematopoietic stem cells (HSCs) using an inhibitory CAR targeting endomucin, a protective antigen unique to healthy HSCs. NK cells with the combined OR-NOT gene circuit kill multiple AML subtypes and protect primary HSCs, and the circuit also works in vivo.

Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: an experimental and immunohistochemical study.

OBJECTIVE: Radioiodine-131 is a radionuclide that is used for therapeutic purposes in hyperthyroidism and thyroid cancer. The aim of this study was to evaluate apoptotosis and proliferative changes in radioiodine-related kidney damage. MATERIALS AND METHODS: Three groups (n=10/group) of rats were used as follows: the rats were in group 1 untreated, and the rats in groups 2 and 3 were treated once with oral radioiodine (111 MBq). The animals in group 2 were killed at the end of the seventh day and the rats in group 3 were killed at the end of the 10th week. The kidneys were removed and evaluated immunohistochemically. The presence of radioiodine in the kidneys was shown by the Na+/I-symporter antibody and proliferating cell nuclear antigen, Ki-67, caspase-3, caspase-8, caspase-9, and terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay were used to detect cell proliferation and apoptosis. RESULTS: Na+/I-symporter protein accumulation in the kidneys was observed to be significantly greater in group 2 than in group 3 (P<0.05). All the immunohistochemical analyses showed that cell proliferation and apoptosis began on the seventh day and peaked in the 10th week. The proliferating cell nuclear antigen, Ki-67, and caspase expressions and terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling values were all found to be statistically significantly increased in group 3 compared with the other groups (P<0.05). CONCLUSION: Radioiodine caused cell proliferation and apoptosis as shown by immunohistochemistry.

The Urinary Tract Microbiome in Health and Disease.

CONTEXT: The urinary tract, previously considered a sterile body niche, has emerged as the host of an array of bacteria in healthy individuals, revolutionizing the urology research field. OBJECTIVE: To review the literature on microbiome implications in the urinary tract and the usefulness of probiotics/prebiotics and diet as treatment for urologic disorders. EVIDENCE ACQUISITION: A systematic review was conducted using PubMed and Medline from inception until July 2016. The initial search identified 1419 studies and 89 were included in this systematic review. EVIDENCE SYNTHESIS: Specific bacterial communities have been found in the healthy urinary tract. Changes in this microbiome have been observed in certain urologic disorders such as urinary incontinence, urologic cancers, interstitial cystitis, neurogenic bladder dysfunction, sexually transmitted infections, and chronic prostatitis/chronic pelvic pain syndrome. The role of probiotics, prebiotics, and diet as treatment or preventive agents for urologic disorders requires further investigation. CONCLUSIONS: There is a microbiome associated with the healthy urinary tract that can change in urologic disorders. This represents a propitious context to identify new diagnostic, prognostic, and predictive microbiome-based biomarkers that could be used in clinical urology practice. In addition, probiotics, prebiotics, and diet modifications appear to represent an opportunity to regulate the urinary microbiome. PATIENT SUMMARY: We review the urinary microbiome of healthy individuals and its changes in relation to urinary disorders. The question to resolve is how we can modulate the microbiome to improve urinary tract health.

Familial Mediterranean fever in childhood: a single-center experience.

The aim of this study is to present demographic and clinical features, MEFV mutation variations, and treatment response of a large number of pediatric familial Mediterranean fever (FMF) patients from a single tertiary centre. Moreover, we aimed to investigate the current outcome of FMF, namely frequency of amyloidosis in children with FMF. We evaluated 708 FMF patients who were followed up in our clinic and who were under colchicine treatment for at least 6 months. The data were recorded from patient records and also verified by negotiations with patients and parents. The male/female proportion of the cohort was 1.05/1 (n = 362/346). Abdominal pain (89.5%, n = 634) was the most common manifestation of FMF episodes, followed by fever (88.8%, n = 629) and arthritis (40.7%, n = 288). However, arthritis in 23 (8%) of the 288 cases was not self-limited; and they subsequently diagnosed with juvenile idiopathic arthritis in addition to FMF. Homozygote or heterozygote M694V mutation was more frequent in patients with arthritis (63.2%) and chronic arthritis (69.6%) than the whole cohort (53.8%). Erythrocyte sedimentation rate and CRP level were in high levels even during attack-free period in 13.9% (n = 97/697) and 11% (n = 78/670) of the patients, respectively. Proteinuria was found in ten patients (1.4%). Amyloidosis was confirmed by renal biopsy in only two of these cases who were homozygous for M694V and compound heterozygous for M694V/M680I. 47 (6.6%) subjects were considered as colchicine resistant. Homozygote M694V mutation was the most frequent mutation in those resistant cases (63.8%, n = 30), followed by compound heterozygote mutation of M694V/M680I (6.3%, n = 3). Homozygous M694V mutation are still the most frequent mutation and associated with the most severe clinical picture and the worst outcome in Turkish children. M694V genotype seems to be more frequently associated with arthritis as well as with chronic arthritis than other genotypes. Recurrence of FMF episodes as well as amyloidosis could only be managed via strict compliance to colchicine treatment. Frequency of amyloidosis significantly decreased compared to the previous studies. A favorable outcome could be obtained with the anti IL-1 in colchicine-resistant FMF patients.

Dietary Fructose-Induced Hepatic Injury in Male and Female Rats: Influence of Resveratrol.

Purpose: Relatively little is known about gender-dependent susceptibility to hepatic injury induced by nutritional factors. In the current study, we investigated dietary fructose-induced hepatic degeneration and roles of endothelial nitric oxide synthase (eNOS), insulin receptor (IRß) and substrate-1 (IRS-1) expressions in association with inflammatory markers in male and female rats. Moreover, we examined potential effect of resveratrol on fructose-induced changes. Methods: Male and female rats were divided into 4 groups as control, resveratrol, fructose and resveratrol plus fructose. All rats were fed with a standard diet with or without resveratrol (500 mg/kg). Fructose was given as 10% in drinking waterfor 24 weeks. Results: Long-term dietary fructose caused parenchymal degeneration and hyperemia in association with impaired eNOS mRNA/protein expressions in liver of male and female rats. This dietary intervention also led to increases in hepatic triglyceride content, TNFα and IL-1ß levels in both genders. Gender-related differences to consequence of fructose consumption were not obvious. Resveratrol supplementation markedly attenuated hepatic degeneration, hyperemia and triglyceride content in association with reduced TNFα and IL-1ß levels, but enhanced IRß mRNA and IRS-1 protein, in male and female rats upon fructose feeding. Conclusion: Long-term dietary fructose causes hepatic degeneration possibly via a decrease in eNOS, but increase in TNFα and IL-1ß, in both genders. Resveratrol supplementation improved fructose-induced hepatic injury.

Bovine papillomavirus type 2 infection and microscopic patterns of urothelial tumors of the urinary bladder in water buffaloes.

Microscopic patterns of thirty-four urothelial tumors of the urinary bladder of water buffaloes from the Marmara and Black Sea Regions of Turkey are here described. All the animals grazed on lands rich in bracken fern. Histological diagnosis was assessed using morphological parameters recently suggested for the urinary bladder tumors of cattle. Papillary carcinoma was the most common neoplastic lesion (22/34) observed in this study, and low-grade carcinoma was more common (seventeen cases) than high-grade carcinoma (five cases). Papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and invasive carcinomas were less frequently seen. Carcinoma in situ (CIS) was often detected associated with some papillary and invasive carcinomas. De novo (primary) CIS was rare representing 3% of tumors of this series. A peculiar feature of the most urothelial tumors was the presence in the tumor stroma of immune cells anatomically organized in tertiary lymphoid organs (TLOs). Bovine papillomavirus type-2 (PV-2) E5 oncoprotein was detected by molecular and immunohistochemistry procedures. Early protein, E2, and late protein, L1, were also detected by immunohistochemical studies. Morphological and molecular findings show that BPV-2 infection contributes to the development of urothelial bladder carcinogenesis also in water buffaloes.