Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.
Increased stiffness of solid tissues has long been recognized as a diagnostic feature of several pathologies, most notably malignant diseases. In fact, it is now well established that elevated tissue rigidity enhances disease progression and aggressiveness and is associated with a poor prognosis in patients as documented, for instance, for lung fibrosis or the highly desmoplastic cancer of the pancreas. The underlying mechanisms of the interplay between physical properties and cellular behavior are, however, not very well understood. Here, we have found that switching culture conditions from soft to stiff substrates is sufficient to evoke (macro) autophagy in various fibroblast types. Mechanistically, this is brought about by stiffness-sensing through an Integrin αV–focal adhesion kinase module resulting in sequestration and posttranslational stabilization of the metabolic master regulator AMPKα at focal adhesions, leading to the subsequent induction of autophagy. Importantly, stiffness-induced autophagy in stromal cells such as fibroblasts and stellate cells critically supports growth of adjacent cancer cells in vitro and in vivo. This process is Integrin αV dependent, opening possibilities for targeting tumor-stroma crosstalk. Our data thus reveal that the mere change in mechanical tissue properties is sufficient to metabolically reprogram stromal cell populations, generating a tumor-supportive metabolic niche.
Purpose To describe the perfusion patterns of peripheral pulmonary granulomatous lesions (PPGLs) by contrast‐enhanced ultrasound (CEUS) and their correlation with vascularization patterns (VPs) represented by immunohistochemical (CD34) endothelial staining. Patients and methods From January 2007 until September 2020, 10 consecutive patients with histologically confirmed PPGLs were investigated by CEUS. The time to enhancement, classified as early pulmonary‐arterial (PA) pattern of enhancement versus delayed bronchial‐arterial (BA) pattern of enhancement, the extent of enhancement, classified as marked or reduced, the homogeneity of enhancement, classified as homogeneous or inhomogeneous, and the decrease of enhancement, classified as rapid washout (<120 seconds) or a late washout (≥120 seconds), were analyzed retrospectively. Furthermore, the tissue samples from the study patients and as a control group, 10 samples of normal lung tissue obtained by autopsy, and 10 samples of lung tissue with acute pneumonia obtained by autopsy were immunohistochemically stained with CD34 antibody. The presence of avascular areas (AAs) and the VPs were evaluated in all tissue samples. Results On CEUS, all PPGLs showed a reduced inhomogeneous BA pattern of enhancement and a rapid washout (<120 seconds). On CD34 staining, all PPGLs showed central AAs in granulomas and a chaotic VP similar to angiogenesis in lung tumors. The lung tissue in control groups revealed on CD34 staining a regular alveolar VP. Conclusion The PPGLs on CEUS show an identical perfusion pattern similar to those of malignant lesions. Furthermore, for the first time, neoangiogenesis was demonstrated as a histopathological correlate to BA pattern of enhancement on CEUS.
Purpose To describe perfusion patterns of peripheral pulmonary lesions (PPLs) in COVID‐19 patients using contrast‐enhanced ultrasound (CEUS). Patients and methods From April 2020 until July 2020, 11 consecutive patients with RT‐PCR‐confirmed COVID‐19 and PPLs sized over 5 mm were investigated by B‐mode ultrasound (B‐US) and CEUS. The homogeneity of enhancement (homogeneous and inhomogeneous) was examined retrospectively using CEUS. An inhomogeneous enhancement was defined as a perfused lesion with coexisting non‐perfused areas (NPA). Results On B‐US, all 11 patients showed an interstitial syndrome (B‐lines) with PPLs between 0.5 and 6 cm. On CEUS, all cases showed peripheral NPA during the complete CEUS examination. One patient underwent a partial lung resection with subsequent histopathological examination. The histological examination showed vasculitis, microthrombus in the alveolar capillary, and small obliterated vessels. Conclusion In our case series, PPLs in patients with RT‐PCR‐confirmed COVID‐19 infection presented a CEUS pattern with NPA during the complete CEUS examination. Our findings suggest a peripheral pulmonary perfusion disturbance in patients with COVID‐19 infection. In 1 case, the histopathological correlation with the perfusion disturbance in the PPL was proven.
The p14ARF protein is a well‐known regulator of p53‐dependent and p53‐independent tumor‐suppressive activities. In unstressed cells, p14ARF is predominantly sequestered in the nucleoli, bound to its nucleolar interaction partner NPM. Upon genotoxic stress, p14ARF undergoes an immediate redistribution to the nucleo‐ and cytoplasm, where it promotes activation of cell cycle arrest and apoptosis. Here, we identify p14ARF as a novel interaction partner and substrate of PRMT1 (protein arginine methyltransferase 1). PRMT1 methylates several arginine residues in the C‐terminal nuclear/nucleolar localization sequence (NLS/NoLS) of p14ARF. In the absence of cellular stress, these arginines are crucial for nucleolar localization of p14ARF. Genotoxic stress causes augmented interaction between PRMT1 and p14ARF, accompanied by arginine methylation of p14ARF. PRMT1‐dependent NLS/NoLS methylation promotes the release of p14ARF from NPM and nucleolar sequestration, subsequently leading to p53‐independent apoptosis. This PRMT1‐p14ARF cooperation is cancer‐relevant and indicative for PDAC (pancreatic ductal adenocarcinoma) prognosis and chemotherapy response of pancreatic tumor cells. Our data reveal that PRMT1‐mediated arginine methylation is an important trigger for p14ARF’s stress‐induced tumor‐suppressive function.
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