Platelet- derived growth factor receptor-beta and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study

INTRODUCTION: Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-beta (PDGFR-beta) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-beta (pPDGFR-beta) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation. METHODS: Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity. RESULTS: All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-beta-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals. CONCLUSIONS: PDGFR-beta-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-beta immunoreactivity pattern is not paralleled by pPDGFR-beta or PDGF-B patterns. PDGFR-beta- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls

The one‐carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation

The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner. Furthermore, repair of IR-induced DNA double-strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR-induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2-depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy

Avian mite dermatitis: Diagnostic challenges and unmet needs

The avian mite Dermanyssus gallinae (poultry red mite, PRM) is of major economic and veterinary importance for the poultry and egg industry worldwide. The accumulating reports on the opportunistic nonavian feeding of D. gallinae raise concerns on PRM host expansion. However, the consequent threats to human health remain largely unclear. PRM infestation in humans is usually manifested as a local or generalized noncharacteristic skin reaction referred to as gamasoidosis. This report presents the current state of the art and the new developments on PRM-associated dermatitis, sharing neither the authors’ personal experience nor focusing on differential diagnosis. Specifically, it reflects the outcome of the critical assessment of the available literature by European medical and veterinary experts in the field under the “One Health” approach. © 2018 John Wiley & Sons Lt

Avian mite dermatitis: Diagnostic challenges and unmet needs

The avian mite Dermanyssus gallinae (poultry red mite, PRM) is of major economic and veterinary importance for the poultry and egg industry worldwide. The accumulating reports on the opportunistic nonavian feeding of D. gallinae raise concerns on PRM host expansion. However, the consequent threats to human health remain largely unclear. PRM infestation in humans is usually manifested as a local or generalized noncharacteristic skin reaction referred to as gamasoidosis. This report presents the current state of the art and the new developments on PRM-associated dermatitis, sharing neither the authors’ personal experience nor focusing on differential diagnosis. Specifically, it reflects the outcome of the critical assessment of the available literature by European medical and veterinary experts in the field under the “One Health” approach. © 2018 John Wiley & Sons Lt

Avian mite dermatitis:Diagnostic challenges and unmet needs

The avian mite Dermanyssus gallinae (poultry red mite, PRM) is of major economic and veterinary importance for the poultry and egg industry worldwide. The accumulating reports on the opportunistic nonavian feeding of D. gallinae raise concerns on PRM host expansion. However, the consequent threats to human health remain largely unclear. PRM infestation in humans is usually manifested as a local or generalized noncharacteristic skin reaction referred to as gamasoidosis. This report presents the current state of the art and the new developments on PRM‐associated dermatitis, sharing neither the authors’ personal experience nor focusing on differential diagnosis. Specifically, it reflects the outcome of the critical assessment of the available literature by European medical and veterinary experts in the field under the “One Health” approach