Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations.

Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1 ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue-specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.

Atypical haemolytic uremic syndrome in a patient with severe Babesiosis.

Babesiosis is a tick-borne parasitic infection that can result in various haematological complications. This case report discusses a patient with severe Babesiosis complicated by an unorthodox presentation of Babesiosis-associated haemolytic uremic syndrome. Discussed here is the patient's clinical course and the management strategies employed, with an emphasis on early recognition and treatment of renal failure in the context of severe Babesiosis. Haematologic manifestations of Babesia are common and the severity of disease is dependent on parasite load. While treatment options such as red blood cell exchange have been proposed for severe cases, their impact on clinical outcomes is limited and they may not be readily available in resource-limited settings. Traditional management using antimicrobials has been proposed but there is limited discussion about managing unique presentations such as renal failure in Babesiosis. Hence, understanding the pathophysiology, early recognition and aggressive treatment strategies can optimise clinical outcomes and reduce mortality.

Aortitis presenting as acute myeloid leukemia - A case report.

Introduction: Aortitis can be an initial presentation of many diseases, but most often include large cell vasculitis. Case presentation: We present a case of a 53 year old female who presented with a myriad of symptoms including abdominal pain, nausea, fever, and headaches. CT scan of the chest showed an inflamed aorta with an initial concern for a large cell vasculitis, but found later to be from her underlying acute myeloid leukemia (AML). Discussion/conclusion: Our case emphasizes the importance of aortitis being the initial presentation of a multitude of diseases including malignancy. It remains important, especially for rheumatologists, to consider blood cancers when presented with aortitis. Background/introduction: Aortitis can be an initial presentation of many diseases, but most often include large cell vasculitis. We describe a case of aoritis being the initial presentation of AML. Methods: SCARE 2020 Guidelines.

Raloxifene is a Female-specific Proteostasis Therapeutic in the Spinal Cord.

Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases.

A Fetal-type Variant Posterior Communicating Artery and its Clinical Significance.

The fetal posterior communicating artery is a well-established variant of the cerebral vasculature, occurring in 4-29% of the population. This variant can provide unique challenges in the identification and treatment of cerebrovascular disease or a cerebrovascular accident. Here we present a cadaveric case showing the presence of the fetal-type posterior communicating artery with a contralateral calcified internal carotid artery and discuss the importance of understanding this embryological variant. This case provides specific and unique clinical sequelae that require treatment to be initiated while understanding the various complications that may arise.

SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation.

We previously reported that the dismutase SOD1 is overexpressed in breast cancer. However, whether SOD1 plays an active role in tumor formation in vivo has never been demonstrated. Further, as luminal cells of normal breast epithelial cells are enriched in SOD1, whether SOD1 is essential for normal mammary gland development has never been determined. We initiated this study to investigate the role of SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. We crossed the inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgenic mice to the SOD1 heterozygote or knockout mice. Our results show that SOD1 is essential for oncogene-driven proliferation, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues such as skin and intestines. We show that activation of the oncogene ErbB2 is associated with increased ROS and that high ROS sub-population of ErbB2 cancer cells show elevated SOD1. In the same cells, decrease in SOD1 is associated with an elevation in both apoptosis as well as oncogene-induced senescence. Based on these results, we suggest that SOD1 carries a housekeeping function that maintains ROS levels below a threshold that supports oncogene-dependent proliferation, while allowing escape from oncogene-induced senescence, independently of the oncogene driving tumor formation. These results identify SOD1 as an ideal target for cancer therapy as SOD1 inhibitors hold the potential to prevent the growth of cancers cells of diverse genotypes, activate multiple modes of cell death therefore making acquired resistance more difficult, while sparing normal tissues.

Morbidity Pattern and Role of Community Health Workers in Urban Slums of Durg and Bhilai City of Chhattisgarh.

INTRODUCTION: In 2002, the Government of Chhattisgarh initiated a Community Health Worker program called the Mitanin Program, to strengthen the health system of Chhattisgarh. The current study was conducted with the twin objectives to assess morbidity pattern and health-seeking behavior in urban slums of Durg and Bhilai to understand the role of Mitanins in health seeking of their slum population. METHODS: Ten urban slums, five each from Durg and Bhilai were selected through simple random sampling for the study. Household survey was done using prestructured questionnaire. A total of 1025 households representing 4997 family members were surveyed. RESULTS: The study found that diseases which were most prevalent in the urban slums of Durg and Bhilai are blood pressure and diabetes mellitus. Diseases such as diarrhea, typhoid, hepatitis, tuberculosis, leprosy, and filariasis which have strong association with safe drinking water and sanitation are prevalent. For chronic communicable disease and reproductive and child health (RCH), people from both cities prefer going to public health-care facilities. About a fourth of the population came in contact with the Mitanins to seek health care mostly in relation to chronic communicable diseases and RCH. CONCLUSION: The study shows an increase in the prevalence of chronic lifestyle diseases among the slum population. There is a case for inclusion of chronic conditions, as specified under Comprehensive Primary Health Care. There is a need to reprioritize Mitanin's role in early diagnosis through point-of-care diagnostics and ensuring prompt referrals and follow-up.

Patient-derived Interstitial Fluids and Predisposition to Aggressive Sporadic Breast Cancer through Collagen Remodeling and Inactivation of p53.

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells.Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation.Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446-59. ©2017 AACR.