Induced pluripotent stem cells from Huntington's disease patients:a promising approach to define and correct disease-related alterations

Adult somatic cells such as skin or blood cells from either health donors or patients can be reprogrammed into induced pluripotent stem cells(iPSCs).Given their unlimited self-renewal and differentiation capacities,iPSCs are an invaluable resource to generate terminally differentiated cells.Thus,iPSCs can facilitate the study of human diseases and drug screening,holding great promise for regenerative medicine.Another significant advantage of iPSC disease-modeling is that normal and mutant proteins are expressed at endogenous levels.In addition,subtle phenotypes and the effects of genetic background variations can be assessed by comparison between iPSC lines obtained from different patients and healthy donors as well as isogenic lines,in which disease-related mutations are corrected.

Endoscopic hemostasis makes the difference:Angiographic treatment in patients with lower gastrointestinal bleeding

BACKGROUND The large majority of gastrointestinal bleedings subside on their own or after endoscopic treatment.However,a small number of these may pose a challenge in terms of therapy because the patients develop hemodynamic instability,and endoscopy does not achieve adequate hemostasis.Interventional radiology supplemented with catheter angiography(CA)and transarterial embolization have gained importance in recent times.AIM To evaluate clinical predictors for angiography in patients with lower gastrointestinal bleeding(LGIB).METHODS We compared two groups of patients in a retrospective analysis.One group had been treated for more than 10 years with CA for LGIB(n=41).The control group had undergone non-endoscopic or endoscopic treatment for two years and been registered in a bleeding registry(n=92).The differences between the two groups were analyzed using decision trees with the goal of defining clear rules for optimal treatment.RESULTS Patients in the CA group had a higher shock index,a higher Glasgow-Blatchford bleeding score(GBS),lower serum hemoglobin levels,and more rarely achieved hemostasis in primary endoscopy.These patients needed more transfusions,had longer hospital stays,and had to undergo subsequent surgery more frequently(P<0.001).CONCLUSION Endoscopic hemostasis proved to be the crucial difference between the two patient groups.Primary endoscopic hemostasis,along with GBS and the number of transfusions,would permit a stratification of risks.After prospective confirmation of the present findings,the use of decision trees would permit the identification of patients at risk for subsequent diagnosis and treatment based on interventional radiology.

Physical activity and cardiometabolic risk factors in sprint and jump-trained masters athletes,young athletes and non-physically active men

Objectives Assessing physical activity and cardiometabolic risk in masters athletes as an example of very high physical activity at old age.Methods Forty-three men were studied in full factorial design,either as sprint or jump-trained masters athletes(MA,n=10,age 60–75 years),as young sprint or jump-trained athletes(YA,n=10,age 20–35 years),older control participants(OC,n=11,age 60–75 years)or as young control participants(AC,n=12,age 20–35 years).We performed bio-electrical impedance analysis and assessed serum markers of lipids and glucose metabolism and C-reactive protein,structured training hours,and habitual activity via mobile actimetry.Results Body fat was greater in OC than in MA(23.9[SD 4.2]%vs.14.0[SD 5.7]%,p<0.001),and also greater than in YA and YC(both p<0.001).Weekly training hours were comparable between MA and YA(7.9[SD3.3]hours vs.11.1[SD 4.8]hours,p=0.69).Habitual walking distance was greater in MA than in OC(7,387[SD 4,923]m/day vs.4,110[SD 1,772]m/day,p=0.039),and so was habitual running distance(667[SD690]m/day vs.132[427]m/day,p<0.001).HOMA-index was greater in OC than in MA(2.07[SD 1.39]vs.0.80[SD 0.41],p=0.0039),and so was C-reactive protein(1.35[SD 1.74]mg/l vs.0.58[SD 0.27]mg/ml,p=0.018),whereas serum lipids showed only moderate or no effect(all p between 0.036 and 0.07).Conclusions Improved body composition and physical activity levels in MA are associated with lower cardiometabolic risk,which seems more pronounced for insulin sensitivity and inflammaging than for lipid metabolism.

Janus-faced Mitofusin 2 (MFN2): mitochondria-endoplasmic reticulum shaping and tethering functions unveiled

In a recently published study in Science,Naòn et al.report two uncharacterized splice variants of Mitofusin 2(MFN2)that specifically shape and tether the endoplasmic reticulum(ER)to mitochondria.1 This work sheds new light on the pleiotropic effects previously ascribed to MFN2 loss-of-function mutations,and has important implications for associated metabolic and neurological diseases.

BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells

Recent studies reveal a critical role of tumor cell-released extracellular vesicles(EVs)in pancreatic cancer(PC)progression.However,driver genes that direct EV function,the EV-recipient cells,and their cellular response to EV uptake remain to be identified.Therefore,we studied the role of Bcl-2-associated-anthanogene 6(BAG6),a regulator of EV biogenesis for cancer progression.We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient background.In vivo data were validated using mouse and human organoids and patient samples.Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release.Mechanistically,this was attributed to mast cell(MC)activation via EV-associated IL33.Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration.Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73.Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance.The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC.Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth.MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.