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nant change of this disease may be limited. These results suggest that conservative management may be an option for clinical lobular endocervical glandular hyperplasia.

An increase in tumor size and worsening cytology are important parameters for detecting malignant transformation of lobular endocervical glandular hyperplasia during follow-up. However, the frequency of malignant change of this disease may be limited. These results suggest that conservative management may be an option for clinical lobular endocervical glandular hyperplasia.Genetic alterations of CYLD lysine 63 deubiquitinase (CYLD), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic CYLD alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma), CYLD alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function CYLD alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of CYLD somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor CYLD alterations are also discussed. IMPLICATIONS Alterations in CYLD gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.

Dabrafenib, an inhibitor of mutated

, has significant clinical activity in melanoma patients but is linked to a spectrum of cutaneous toxicities. Thus, our meta-analysis was conducted to evaluate the type, incidence and risks of dermatological toxicities from dabrafenib.

Systematic searches were performed using electronic databases such as Embase and PubMed and conference abstracts published by the American Society of Clinical Oncology. Eligible studies were limited to prospective phase I, II and III clinical trials and expanded-access (ie, outside clinical trials) programmes of melanoma patients receiving dabrafenib monotherapy (150 mg, twice daily) or combination therapy of dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily). The outcomes were mainly the incidence rate and risk of all-grade cutaneous toxicities associated with dabrafenib in melanoma patients.

Twenty trials comprising a total of 3359 patients were included in the meta-analysis. The meta-analysis showed that the overal cSCC, alopecia, KA, HK and pruritus. There was a significantly decreased risk of cSCC, alopecia and HK with the combination of dabrafenib with trametinib versus dabrafenib alone. Clinicians should be aware of these risks and perform regular clinical monitoring.

In summary, the most frequent cutaneous adverse reactions from dabrafenib were rash, cSCC, alopecia, KA, HK and pruritus. There was a significantly decreased risk of cSCC, alopecia and HK with the combination of dabrafenib with trametinib versus dabrafenib alone. Clinicians should be aware of these risks and perform regular clinical monitoring.

Renal tubular injury contributes to the decline in kidney function in patients with diabetes. Cell type-specific DNA methylation patterns have been used to calculate proportions of particular cell types. In this study, we developed a method to detect renal tubular injury in patients with diabetes by detecting exfoliated tubular cells shed into the urine based on tubular cell-specific DNA methylation patterns.

We identified DNA methylation patterns specific for human renal proximal tubular cells through compartment-specific methylome analysis. We next determined the methylation levels of proximal tubule-specific loci in urine sediment of patients with diabetes and analyzed correlation with clinical variables.

We identified genomic loci in

and

to be selectively unmethylated in human proximal tubular cells. The methylation levels of

and

in urine sediment, deemed to reflect the proportion of exfoliated proximal tubular cells due to injury, correlated well with each other. Methylation levels of

in urine sediment significantly correlated with the annual decline in estimated glomerular filtration rate. Moreover, addition of urinary

methylation to a model containing known risk factors significantly improved discrimination of patients with diabetes with faster estimated glomerular filtration rate decline.

This study demonstrates that patients with diabetes with continual loss in kidney function may be stratified by a specific DNA methylation signature through epigenetic urinalysis and provides further evidence at the level of exfoliated cells in the urine that injury of proximal tubular cells may contribute to pathogenesis of diabetic kidney disease.

This study demonstrates that patients with diabetes with continual loss in kidney function may be stratified by a specific DNA methylation signature through epigenetic urinalysis and provides further evidence at the level of exfoliated cells in the urine that injury of proximal tubular cells may contribute to pathogenesis of diabetic kidney disease.

Obesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease. T2DM increases the risk of cardiovascular-related death. We investigated changes in circulating exosomal microRNA (miRNA) profiles in patients with DM with obesity compared with patients without DM with obesity.

This prospective study involved 29 patients with obesity (patients without DM=16, patients with DM=13) and healthy volunteers (HVs) (n=18). We measured circulating levels of exosomal miRNAs by next-generation sequencing and compared miRNA levels across the three groups.

The expression levels of 25 miRNAs (upregulated=14, downregulated=11) differed between patients with obesity with DM and patients with obesity without DM. Compared with HV, patients with DM with obesity had 53 dysregulated miRNAs. Additionally, moving stepwise from HV to patients with obesity without DM to patients with obesity with DM, there was a consistent increase in expression levels of miR-23a-5p and miR-6087 and a consistent decrease in expressions levels of miR-6751-3p.

Our data show that the exosomal miRNAs is altered by dysregulated glucose metabolism in patients with obesity. This circulating exosomal miRNA signature in patients with obesity with or without DM is a potential biomarker and therapeutic target in these patients.

Our data show that the exosomal miRNAs is altered by dysregulated glucose metabolism in patients with obesity. This circulating exosomal miRNA signature in patients with obesity with or without DM is a potential biomarker and therapeutic target in these patients.

Treatment using sodium-glucose cotransporter (SGLT) 2 inhibitor and low-carbohydrate diet (LCD) for obesity and type 2 diabetes are similar in terms of carbohydrate limitation. However, their mechanisms of action differ, and the effects on the body remain unclear. We investigated the effects of SGLT2 inhibitor and LCD on body composition and metabolic profile using the

mouse model for obesity and type 2 diabetes.

Eight-week-old male

mice were divided into four groups mice receiving normal diet and vehicle or canagliflozin (Cana) administration and mice receiving LCD and vehicle or Cana administration for 8 weeks. Consumed calories were adjusted to be equal among the groups.

Both Cana administration and LCD feeding resulted in significant weight gain. Cana administration significantly decreased plasma glucose levels and increased plasma insulin levels with preservation of pancreatic β cells. However, LCD feeding did not improve plasma glucose levels but deteriorated insulin sensitivity. LCD feeding significantly reduced liver weight and hepatic triglyceride content; these effects were not observed with Cana administration. Combined treatment with LCD did not lead to an additive increase in blood β-ketone levels.

SGLT2 inhibitors and LCD exert differential effects on the body. Their combined use may achieve better metabolic improvements in obesity and type 2 diabetes.

SGLT2 inhibitors and LCD exert differential effects on the body. find more Their combined use may achieve better metabolic improvements in obesity and type 2 diabetes.

Tight control of hyperglycemia reduces risk of diabetic retinopathy (DR), but the residual risk remains high. link2 This study aimed to explore relationships between plasma phenylalanine and tyrosine with DR in type 2 diabetes (T2D) and interactions between the two amino acids, and their secondary interaction with renal dysfunction.

We extracted data of 1032 patients with T2D from tertiary hospital consecutively from May 2015 to August 2016. Binary logistic regression models with restricted cubic spline were used to check potential non-linear associations and to obtain ORs and 95% CIs of variables under study. Addictive interaction was estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Area under the receiver operating characteristic curve was used to check increased predictive values.

Of 1032 patients, 162 suffered from DR. Copresence of low phenylalanine and low tyrosine increased DR risk (OR 6.01, 95% CI 1.35 to 26.8), while either of them alone did not have a significant effect with significant additive interaction. Presence of diabetic nephropathy further increased the OR of copresence of low phenylalanine and low tyrosine for DR to 25.9 (95% CI 8.71 to 76.9) with a significant additive interaction. Inclusion of phenylalanine and tyrosine in a traditional risk factor model significantly increased area under the curve from 0.81 to 0.83 (95% CI 0.80 to 0.86).

Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. link3 Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.

Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.