Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease.

Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations.

Targeted deletion of von-Hippel-Lindau in the proximal tubule conditions the kidney against early diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Glomerular hyperfiltration and albuminuria subject the proximal tubule (PT) to a subsequent elevation of workload, growth, and hypoxia. Hypoxia plays an ambiguous role in the development and progression of DKD and shall be clarified in our study.

The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in -Negative Women.

Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as and However, data regarding genetic factors predisposing to CBC among younger women who are -negative remain limited.

Methods: In this nested case-control study, participants negative for // PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC).

VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney.

The lipid kinase VPS34 orchestrates autophagy, endocytosis, and metabolism and is implicated in cancer and metabolic disease. The proximal tubule in the kidney is a key metabolic organ that controls reabsorption of nutrients such as fatty acids, amino acids, sugars, and proteins. Here, by combining metabolomics, proteomics, and phosphoproteomics analyses with functional and superresolution imaging assays of mice with an inducible deficiency in proximal tubular cells, we revealed that VPS34 controlled the metabolome of the proximal tubule.

Novel anatomical findings with implications on the etiology of the piriformis syndrome.

Purpose: The cause of the piriformis-related pelvic and extra-pelvic pain syndromes is still not well understood. Usually, the piriformis syndrome is seen as extra-pelvic sciatica caused by the entrapment of the sciatic nerve by the piriformis in its crossing through the greater sciatic foramen. However, the piriformis muscle may compress additional nerve structures in other regions and cause idiotypic pelvic pain, pelvic visceral pain, pudendal neuralgia, and pelvic organ dysfunction.

Sputum Microbiome Composition in Patients with Squamous Cell Lung Carcinoma.

Background: Recent findings indicate that the host microbiome can have a significant impact on the development of lung cancer by inducing an inflammatory response, causing dysbiosis, and generating genome damage. The aim of this study was to search for bacterial communities specifically associated with squamous cell carcinoma (LUSC).

Methods: In this study, the taxonomic composition of the sputum microbiome of 40 men with untreated LUSC was compared with that of 40 healthy controls.

Sputum Microbiota in Coal Workers Diagnosed with Pneumoconiosis as Revealed by 16S rRNA Gene Sequencing.

Coal worker's pneumoconiosis (CWP) is an occupationally induced progressive fibrotic lung disease. This irreversible but preventable disease currently affects millions across the world, mainly in countries with developed coal mining industries. Here, we report a pilot study that explores the sputum microbiome as a potential non-invasive bacterial biomarker of CWP status.

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs.

Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms: a case series and literature review.

Background: Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking.

Aim: To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs.

The Influence of Virus Infection on Microglia and Accelerated Brain Aging.

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses.

Innervation of the clavicular part of the deltoid muscle by the lateral pectoral nerve.

Introduction: The innervation pattern of the clavicular head of the deltoid muscle and its corresponding topography was investigated via cadaveric dissection in the present study, focusing on the lateral pectoral nerve.

Materials And Methods: Fifty-eight upper extremities were dissected and the nerve supplies to the deltoid muscle and the variability of the lateral pectoral and axillary nerves, including their topographical patterns, were noted.

Results: The clavicular portion of the deltoid muscle received a deltoid branch from the lateral pectoral nerve in 86.

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome.

The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC.

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy.

Background In pregnancy, a high plasma volume maintains uteroplacental perfusion and prevents placental ischemia, a condition linked to elevated maternal blood pressure ( BP ). Reducing BP by increasing Na intake via plasma volume expansion appears contra-intuitive. We hypothesize that an appropriate Na intake in pregnancy reduces maternal BP and adapts the renin-angiotensin system in a pregnancy-specific manner.

Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.

Background: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.

Current Therapies for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients.

The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the first line, followed by the addition of lapatinib and by a switch to another cytotoxic agent after progression. Results of CLEOPATRA, EMILIA, and TH3RESA trials have changed this clinical practice.

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.

mTOR Regulates Endocytosis and Nutrient Transport in Proximal Tubular Cells.

Renal proximal tubular cells constantly recycle nutrients to ensure minimal loss of vital substrates into the urine. Although most of the transport mechanisms have been discovered at the molecular level, little is known about the factors regulating these processes. Here, we show that mTORC1 and mTORC2 specifically and synergistically regulate PTC endocytosis and transport processes.

Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer.

Purpose: Aromatase inhibitors (AIs) have an established role in the treatment of breast cancer. Response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy.

Personalization of loco-regional care for primary breast cancer patients (part 2).

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures.

Personalization of loco-regional care for primary breast cancer patients (part 1).

ABSTRACT  Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures.

Molecular changes in lobular breast cancers in response to endocrine therapy.

Invasive lobular carcinoma (ILC) accounts for approximately 10% to 15% of breast carcinomas, and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre- and on-treatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 postmenopausal women with estrogen receptor-positive (ER(+)) histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding invasive ductal carcinomas (IDC) matched on clinicopathologic features. RNA was extracted and processed for whole human genome expression microarray.

High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients.

In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A.