Microsatellite instability driven metastatic parathyroid carcinoma managed with the anti-PD1 immunotherapy, pembrolizumab.

The present case report describes a 65-year-old man with Lynch syndrome and hypercalcaemia associated with hyperparathyroidism. Parathyroid surgery confirmed the diagnosis of parathyroid carcinoma. Serum calcium and parathyroid hormone (PTH) concentrations serially increased after initial surgery. Imaging study and subsequent biopsy confirmed lung metastases with mismatch repair deficiency. Pembrolizumab was initiated achieving 60% reduction in tumour burden.

Genome and evolution of the shade-requiring medicinal herb Panax ginseng.

Panax ginseng C. A. Meyer, reputed as the king of medicinal herbs, has slow growth, long generation time, low seed production and complicated genome structure that hamper its study. Here, we unveil the genomic architecture of tetraploid P. ginseng by de novo genome assembly, representing 2.98 Gbp with 59 352 annotated genes. Resequencing data indicated that diploid Panax species diverged in association with global warming in Southern Asia, and two North American species evolved via two intercontinental migrations. Two whole genome duplications (WGD) occurred in the family Araliaceae (including Panax) after divergence with the Apiaceae, the more recent one contributing to the ability of P. ginseng to overwinter, enabling it to spread broadly through the Northern Hemisphere. Functional and evolutionary analyses suggest that production of pharmacologically important dammarane-type ginsenosides originated in Panax and are produced largely in shoot tissues and transported to roots; that newly evolved P. ginseng fatty acid desaturases increase freezing tolerance; and that unprecedented retention of chlorophyll a/b binding protein genes enables efficient photosynthesis under low light. A genome-scale metabolic network provides a holistic view of Panax ginsenoside biosynthesis. This study provides valuable resources for improving medicinal values of ginseng either through genomics-assisted breeding or metabolic engineering.

The action of resveratrol, a phytoestrogen found in grapes, on the intervertebral disc.

STUDY DESIGN: Basic science, biologic study. OBJECTIVE: To determine the potential benefits of using resveratrol (RSV) for intervertebral disc (IVD) matrix repair and regeneration. SUMMARY OF BACKGROUND DATA: The phytoestrogen RSV is a natural compound found in various plants including grapes and red wines. RSV has been reported to provide a protective effect on articular cartilage in rabbit models for arthritis, but its effect on spine cartilage is unknown. METHODS.: We studied the effect of RSV on bovine IVD cartilage homeostasis by assessing MMP-13 (potent catabolic factor) production, proteoglycan (PG) accumulation and synthesis, and the interaction between RSV and known catabolic factors such as bFGF or IL-1. To understand the molecular mechanisms by which RSV modulates MMP-13 and PG production, we also investigated its downstream target regulatory molecules. RESULTS: Stimulation of bovine disc cells cultured in monolayer with bFGF or IL-1 augmented the production of MMP-13 and ADAMTS-4 at the transcriptional level and this augmentation was blocked by RSV. Incubation of nucleus pulposus cells with RSV for 21 days significantly increased PG accumulation per cell in a dose-dependent manner, increased PG synthesis, rescued PG losses induced by catabolic reagents bFGF and IL-1, and promoted cell survival to levels seen after incubation with the anabolic protein BMP7 100 ng/mL. Protein-DNA interaction array results suggest that RSV effectively suppresses downstream target molecules of bFGF and IL-1 responsible for oxidative stress, proliferation, and apoptosis. CONCLUSION: Resveratrol is a potent anabolic mediator of bovine IVD cartilage homeostasis, revealing its potential as a unique biologic treatment to slow the progression of IVD degeneration. These data suggests RSV may have considerable promise in the treatment of disc degeneration.

Persistence with once-daily versus twice-daily bupropion for the treatment of depression in a large managed-care population.

In this study, the impact of dosing frequency [once daily with bupropion extended-release (XL) versus twice daily with bupropion sustained-release (SR)] on medication persistence was assessed over a 9-month period in a large cohort of patients with depression in a managed-care setting. Administrative claims data from the Integrated Health Care Information Services National Managed Care Benchmark database were analyzed for patients 18 to 64 years old with a documented diagnosis of depression who began treatment with bupropion XL or SR between September 2003 and February 2004. Persistence of use was higher with once-daily bupropion XL (n = 1074) than with twice-daily bupropion SR (n = 1917) across measures assessed by univariate tests of proportions. The mean (+/-SD) number of days between the first and last prescription claims was longer with bupropion XL (128.37 +/- 103.46 days) than with bupropion SR (82.31 +/- 96.86 days) (P < 0.0001). The bupropion XL cohort had higher persistency of use than the bupropion SR cohort (mean +/- SD = 0.47 +/- 0.38 versus 0.30 +/- 0.36) (P < 0.0001) and a higher medication possession ratio (mean +/- SD = 0.50 +/- 0.33 versus 0.36 +/- 0.31) (P < 0.0001). Medication persistency >0.7 and a medication possession ratio >0.7 were almost twice as likely in the bupropion XL cohort (38.5% and 32.0%, respectively) than in the bupropion SR cohort (21.5% and 17.0%, respectively). Results of multivariate analyses adjusted for age, gender, and index date support the univariate analyses. Because better persistence and adherence may be associated with less likelihood of relapse and lower depression-associated health care utilization and economic burden, health care providers should consider the potential benefits of initiating treatment with bupropion XL for bupropion candidates and for switching bupropion SR recipients to treatment with bupropion XL.

Comparative analysis of ATRX, a chromatin remodeling protein.

The ATRX protein, associated with X-linked alpha-thalassaemia, mental retardation and developmental abnormalities including genital dysgenesis, has been proposed to function as a global transcriptional regulator within a multi-protein complex. However, an understanding of the composition and mechanics of this machinery has remained elusive. We applied inter-specific comparative analysis to identify conserved elements which may be involved in regulating the conformation of chromatin. As part of this study, we cloned and sequenced the entire translatable coding region (7.4 kb) of the ATRX gene from a model marsupial (tammar wallaby, Macropus eugenii). We identify an ATRX ancestral core, conserved between plants, fish and mammals, comprising the cysteine-rich and SWI2/SNF2 helicase-like regions and protein interaction domains. Our data are consistent with the model of the cysteine-rich region as a DNA-binding zinc finger adjacent to a protein-binding (plant homeodomain-like) domain. Alignment of vertebrate ATRX sequences highlights other conserved elements, including a negatively charged mammalian sequence which we propose to be involved in binding of positively charged histone tails.