Multi-Niche Human Bone Marrow On-A-Chip for Studying the Interactions of Adoptive CAR-T Cell Therapies with Multiple Myeloma.

Multiple myeloma (MM), a cancer of bone marrow plasma cells, is the second-most common hematological malignancy. However, despite immunotherapies like chimeric antigen receptor (CAR)-T cells, relapse is nearly universal. The bone marrow (BM) microenvironment influences how MM cells survive, proliferate, and resist treatment. Yet, it is unclear which BM niches give rise to MM pathophysiology. Here, we present a 3D microvascularized culture system, which models the endosteal and perivascular bone marrow niches, allowing us to study MM-stroma interactions in the BM niche and model responses to therapeutic CAR-T cells. We demonstrated the prolonged survival of cell line-based and patient-derived multiple myeloma cells within our in vitro system and successfully flowed in donor-matched CAR-T cells. We then measured T cell survival, differentiation, and cytotoxicity against MM cells using a variety of analysis techniques. Our MM-on-a-chip system could elucidate the role of the BM microenvironment in MM survival and therapeutic evasion and inform the rational design of next-generation therapeutics. TEASER: A multiple myeloma model can study why the disease is still challenging to treat despite options that work well in other cancers.

Fatherhood too soon. Anxiety, depression and quality of life in fathers of preterm and term babies: a longitudinal study.

INTRODUCTION: Fathers are increasingly recognized as playing a critical role in the family unit and emotional development of children. The birth of a preterm baby can be confronting, yet there is limited research that explores how preterm birth might impact on father's emotional wellbeing and quality of life. The aim of the study was to monitor quality of life and psychological wellbeing in a group of fathers to explore if a preterm birth altered outcomes in these two domains. METHODS: Institutional ethics committee approval was obtained. Australian men (N = 1000) were recruited in the antenatal period via their pregnant partner, and completed the Hospital Anxiety and Depression Scale (HADS) and Satisfaction with Life Scale (SWLS) in the third trimester and again 6 weeks after the birth of their baby. Birth records were independently audited to determine which fathers experienced preterm birth. RESULTS: Data was available for 1000 and 950 fathers at each time point. Overall, 72 (7.2%) of fathers experienced preterm birth and 928 (92.8%) had a term birth. Fathers of preterm infants were significantly older (p = 0.002) and less likely to be married or in a defacto relationship (p = 0.043). Preterm babies were more likely to be delivered by cesarean section, have a low birthweight and require admission to a special care or neonatal intensive care unit (p < 0.001). There were no significant differences in HADS total, anxiety or depression subscale and SWLS scores in the antenatal period. Six weeks after the birth, fathers of preterm babies were significantly more likely to meet the case criteria for anxiety compared to fathers of term babies (25 vs. 12%, p = 0.02). This was due to persisting anxiety in preterm fathers (p < 0.001). They also reported significantly lower SWLS scores compared to fathers of term infants (27.31 vs. 27.88, p = 0.011). However, there were no differences in depression or HADS total scores. CONCLUSION: Following birth of a preterm baby, persisting anxiety may affect quality of life of fathers. Routine screening of fathers of preterm babies may identify men who could benefit from referral for psychological intervention.

[Rupture of the spleen following Caesarean section]. / Miltruptur efter sectio.

A case of rupture of the spleen after Caesarean section is presented. Rupture of the spleen is a rare complication of pregnancy. The aetiology of splenic rupture is discussed. It is important to keep this rare condition in mind. Fast intervention limits the effects of this potentially lethal condition.

Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect.

In myotubes established from patients with type 2 diabetes (T2D), lipid oxidation and insulin-mediated glucose oxidation are reduced, whereas in myotubes from obese non-diabetic subjects, exposure to palmitate impairs insulin-mediated glucose oxidation. To determine the underlying mechanisms of these metabolic malfunctions, we studied mitochondrial respiration, uncoupled respiration and oxidative enzyme activities (citrate synthase (CS), 3-hydroxy-acyl-CoA-dehydrogenase activity (HAD)) before and after acute exposure to insulin and/or palmitate in myotubes established from healthy lean and obese subjects and T2D patients. Basal CS activity was lower (14%) in diabetic myotubes compared with myotubes from lean controls (P=0.03). Incubation with insulin (1 microM) for 4 h increased the CS activity (26-33%) in myotubes from both lean (P=0.02) and obese controls (P<0.001), but not from diabetic subjects. Co-incubation with palmitate (0.6 mM) for 4 h abolished the stimulatory effect of insulin on CS activity in non-diabetic myotubes. No differences were detected in mitochondrial respiration and HAD activity between myotubes from non-diabetic subjects and T2D patients, and none of these measures responded to high levels of insulin and/or palmitate. These results provide evidence for an intrinsic defect in CS activity, which may play a role in the pathogenesis of T2D. Moreover, the data suggest that insulin resistance at the CS level can be induced by exposure to high free fatty acid levels.

The diabetic phenotype is conserved in myotubes established from diabetic subjects: evidence for primary defects in glucose transport and glycogen synthase activity.

The most well-described defect in the pathophysiology of type 2 diabetes is reduced insulin-mediated glycogen synthesis in skeletal muscles. It is unclear whether this defect is primary or acquired secondary to dyslipidemia, hyperinsulinemia, or hyperglycemia. We determined the glycogen synthase (GS) activity; the content of glucose-6-phosphate, glucose, and glycogen; and the glucose transport in satellite cell cultures established from diabetic and control subjects. Myotubes were precultured in increasing insulin concentrations for 4 days and subsequently stimulated acutely by insulin. The present study shows that the basal glucose uptake as well as insulin-stimulated GS activity is reduced in satellite cell cultures established from patients with type 2 diabetes. Moreover, increasing insulin concentrations could compensate for the reduced GS activity to a certain extent, whereas chronic supraphysiological insulin concentrations induced insulin resistance in GS and glucose transport activity. Our data suggest that insulin resistance in patients with type 2 diabetes comprises at least two important defects under physiological insulin concentrations: a reduced glucose transport under basal conditions and a reduced GS activity under acute insulin stimulation, implicating a reduced glucose uptake in the fasting state and a diminished insulin-mediated storage of glucose as glycogen after a meal.