SUMMARY Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Bone marrow edema is a potent risk factor for structural deterioration in knee osteoarthritis, and its relation to progression is explained in part by its association with limb alignment.

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genomewide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10 −27 ) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10 −9 ). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T 4 ) and high concentration of triiodothyronine (T 3 ).Thyroid carcinoma is the most common endocrine malignancy, and its incidence in industrialized countries has been rising over the past few decades: at present, its incidence is 4.9 and 14.1 per 100,000 in the United States for males and females of European ancestry, respectively (see URLs section in Methods). It has been determined that the risk of thyroid cancer has a greater genetic component than the risk of any other cancer, and the effect has been shown to extend beyond the nuclear family 1-3 . The risk has been reported to be highest for first-degree male relatives of male probands but lowest for first-degree female relatives of female probands 4 . Not much is known about variants in the sequence of the genome that affect the risk of thyroid cancer. However, recently variants at 1p12, 8q24 and in the premiR146a at 5q33 have been implicated in the disease 5-8 .Thyroid cancer is classified histologically into four main groups: papillary (PTC), follicular (FTC), medullary (MTC) and undifferentiated or anaplastic thyroid carcinomas. Most of all thyroid tumors are PTC (80-85%) or FTC (10-15%) 9,10 . Among established risk factors for FTC is deficiency in iodine intake, and for PTC the risk factors include ionizing radiation, nodular disease of the thyroid as well as family history 9 . Medullary thyroid cancer is a part of the multiple endocrine neoplasia type 2 syndrome (MEN2) and accounts for about 1-3% of all thyroid cancer cases. Its pathogenesis can mainly be explained by mutations in the RET oncogene 11 . Anaplastic thyroid cancer accounts for between 1% and 5% of all carcinomas of the thyroid. This subphenotype is one of the most aggressive of all human malignancies, but little is known about its pathogenesis 12 .In Iceland, the annual incidence of thyroid cancer is similar to that in the United States, at 4.6 and 12.1 per 100,000 for males and fe...

OBJECTIVETo examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone.RESEARCH DESIGN AND METHODSTreatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10 mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA1c change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis.RESULTSAt week 24, the mean reduction from baseline in HbA1c was −0.42% for placebo versus −0.82 and −0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7–1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6–9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0–8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1–4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare.CONCLUSIONSIn patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk.