Mechanism of Cyclin D1 regulation by progestins in breast cancer

<p>The majority of breast tumors express the estrogen receptor (ER), and more than half of these cancers also express the progesterone receptor (PR). While the actions of ER on breast cancer pathogenesis are well understood, those of PR are still unclear. The Women's Health Initiative trial in 2002 brought into focus the alarming result that women receiving both estrogen and progestins as hormone replacement therapy are at greater risk for breast cancer than women receiving estrogen alone. Thus, there is considerable interest in defining the mechanisms that underlie the pharmacological actions of progestins in the normal and malignant breast. </p><p>Progestins facilitate cell cycle progression through multiple mechanisms, one of which is the induction of phosphorylation of the tumor suppressor retinoblastoma (Rb) protein. Stimulation by growth factors induces the transcription of Cyclin D1 which in turn activates the cyclin dependent kinases (CDKs). The Cyclin D1- Cdk4/6 complex phosphorylates the Rb protein, leading to the release of E2F1, which then binds and activates other target genes, leading to G1-S transition of the cell cycle. Given the reported action of PR to activate MAPK signaling, we initially thought that the progestin-induced Rb phosphorylation was mediated by this pathway. However, we turned to an alternate hypothesis based on our data using MEK inhibitors demonstrating that this was not the case. </p><p>Given the primacy of Cyclin D1 in cell cycle control, we then turned our attention to defining the mechanism by which Cyclin D1 expression is regulated by PR. Interestingly, it was determined that progestin mediated up- regulation of Cyclin D1 is rapid, peaking at 6hrs post hormone addition followed by a decrease in expression reaching a nadir at 18hrs. Unexpectedly, we found that contrary to what has been published before, the induction of Cyclin D1 mRNA expression was a primary transcriptional event and we have demonstrated the specific interaction of PR with PREs (progesterone response elements) located on this gene. We have further determined that the half-life of Cyclin D1 mRNA is decreased significantly by progestin addition explaining how the levels of this mRNA following the addition of hormone are quickly attenuated. Thus, when taken together, our data suggest that progestins exert both positive and negative effects on Cyclin D1 mRNA, the uncoupling of which is likely to impact the pathogenesis of breast cancer</p><p>The observation that PR reduces the Cyclin D1 mRNA stability led us to investigate the effects of PR on RNA binding proteins, especially those which are involved in RNA stability. We discovered that PR induces the expression of several RNA binding proteins. Although the work to determine the effects of these RNA binding proteins on CyclinD1 mRNA stability is still ongoing, we have discovered a role for one of the PR-induced RNA binding proteins tristetraprolin (TTP), in the suppression of the inflammation pathway in breast cancer. We found that while TTP was not required for the PR-mediated decrease in Cyclin D1 mRNA stability, overexpression of this tumor suppressive protein was able to inhibit IL-1&#946;-mediated stimulation of inflammatory genes in our breast cancer model. Since it is established that the upregulation of the inflammatory pathway is oncogenic, we are currently exploring the intersection of PR and TTP-mediated signaling on the inflammation transcriptome in breast cancer. </p><p>Thus, collectively these data provide us with a better picture of the poorly understood actions of PR on breast cancer proliferation and tumorigenesis. We believe that further investigation of the studies developed in this thesis will lead to novel and better-targeted approaches to the use of PR as a therapeutic target in the clinic.</p>Dissertatio

Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis: Report of a Case and Review of the Literature

Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma. Muir-Torre syndrome is a subset of LS with cutaneous sebaceous adenoma and keratoacanthoma in addition to the malignancies. Renal cell carcinoma (RCC) in patients with LS is extremely rare. Only 26 cases have been reported and among them, only two cases of papillary RCC. We report a case of synchronous papillary RCC and colonic adenocarcinoma in an 85-year-old male with Lynch/Muir-Torre syndrome. The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene. A colonoscopy at that time showed multiple tubular adenomas with high-grade dysplasia. He was lost to follow-up and presented with gastrointestinal bleeding after 20 years. A right colonic mass, and a solid mass in the lower pole of the right kidney, was detected by imaging. Right Colectomy showed a T3N0 mucin-producing adenocarcinoma. Right nephrectomy showed a T3a papillary RCC which was microsatellite stable with MSH6, and KRAS mutation. The 36-month follow-up exams showed additional sebaceous neoplasms, and an absence of metastatic carcinoma. Analysis of the reported cases of RCC in LS show clear cell RCC as the most common type. These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2. Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences

Distributed hardware accelerated secure joint computation on the COPA framework

https://arxiv.org/pdf/2204.04816.pdfFirst author draf

Knowledge, attitudes and practices related to dietary salt intake among adults in North India.

OBJECTIVE: To assess the knowledge, attitudes and practices related to salt consumption among adults in rural and urban North India. DESIGN: Data for the study were obtained from a community-based cross-sectional survey using an interviewer-administered questionnaire and 24 h urine samples. SETTING: Data collection was conducted during March-October 2012 in rural Haryana and urban Delhi in North India. PARTICIPANTS: Adults (n 1635) aged ≥20 years (701 in rural Haryana; 934 in urban Delhi). RESULTS: Twenty-four per cent of rural and 40·5 % of urban participants knew that a high-salt diet causes high blood pressure. Nearly one-fifth of both rural and urban participants knew that there should be a maximum daily limit for consumption of salt. In rural and urban areas, 46·6 and 45·1 %, respectively, perceived it important to reduce the salt content of their diet; however, only 3·7 and 10·2 %, respectively, reported taking some actions. Participants reported they were consuming 'too little salt', 'just the right amount of salt' or 'too much salt', but their corresponding mean (95 % CI) actual salt consumption (g/d; as measured by 24 h urinary Na excretion) was higher, especially among rural participants (rural: 9·2 (8·13, 10·22), 8·5 (8·19, 8·77) or 8·4 (7·72, 8·99); urban: 5·6 (4·67, 6·57), 5·7 (5·32, 6·01) or 4·6 (4·10, 5·14), respectively). CONCLUSIONS: Knowledge about the deleterious health impact of excess salt consumption is low in this population. Tailored public education for salt reduction is warranted with a particular focus on rural residents

Algorithmic Recourse based on User’s Feature-order Preference

The state-of-the-art recourse generation methods solely rely on the user's profile (feature vector). However, two users having the same profile may still have different preferences. Consequently, the recourse generated from a single profile may not have the same appeal to both the users. For example, one rejected loan applicant may prefer changes in Savings Amount, whereas, another - being a financial expert - may prefer changes in Investment Amount. Taking into account these preferences in feature-change can be very helpful in generating more user-satisfying recourses. To this end, we propose a simple user-preference representation and design a method to generate a recourse that adheres to the user preference. We empirically demonstrate the effectiveness and ease of the proposed method at generating recourses satisfying user preferences

Playing with Possibilities

Playing with Possibilitie

Verifying File System Properties with Type Inference

The storage stack is not trustworthy due to errors that arise from a variety of sources: unreliable hardware, malicious errors and file system bugs. Today, software errors play a dominant role due to their inherent complexity. In the first part of our project, we look towards verifying a specific file system property: on-disk pointer manipulation. We utilize CQUAL, a framework for adding type qualifiers with type inference support, and apply our analysis to the Linux ext2 file system. We find that adding qualifiers serves the valuable purpose of ensuring that on-disk pointers are accessed and manipulated correctly by the file system. Thus, we believe that the qualifiers we introduce would decrease the probability of bugs being introduced by file system programmers. We also describe our experience in using CQUAL and discuss its limitations. Based on our experience with CQUAL, we come up with a second analysis, a buffer management verifier, that fits better with the power of CQUAL by being simpler, yet more widely applicable to different file systems than the first analysis

“It’s Partly in our Hands; It’s Partly in the Hands of the Goddess”

As the government and NGO public health campaigns in Tamil Nadu promote biomedical methods of cancer prevention and treatment as “modern” and “rational” approaches to cancer, localized notions that cancer is often a karmic punishment for an immoral act committed in the past or the physical manifestation of a kind of injustice that an adversary renders through the deliberate use of sorcery is being recast as a “backward” and “irrational way of thinking.” Yet women in Tamil Nadu continue to draw from both these ways of understanding cancer. In this paper, we explore how cancer patients and survivors in Tamil Nadu weave the public health discourse together with other sociocultural and religious discourses of cancer to create complex understandings and experiences of social suffering caused by cancer and to find ways to mitigate such suffering. Based on interviews conducted in hospital wards with women cervical and breast cancer patients and survivors, this paper explores how women often experience cancer as a biological, social and spiritual affliction that can be cured only when biomedical modalities of treatment are used in conjunction with religious modalities of healing.Au Tamil Nadu, les campagnes de santé publique lancées par le gouvernement et les ONG promeuvent les méthodes biomédicales de prévention et de traitement du cancer en tant qu’approches « modernes » et « rationnelles » du cancer, ce qui permet de penser que le cancer est souvent une punition karmique pour un acte immoral commis dans le passé. La manifestation physique d’une sorte d’injustice que l’adversaire a provoquée par l’utilisation délibérée de la sorcellerie est en train d’être reformulée comme une façon de penser « arriérée » et « irrationnelle ». Pourtant, les femmes du Tamil Nadu continuent de s’inspirer de ces deux manières de comprendre le cancer. Dans cet article, nous explorons comment les patients et les survivants du Tamil Nadu tissent le discours de la santé publique avec d’autres discours socioculturels et religieux sur le cancer afin de créer une compréhension et des expériences complexes de la souffrance sociale causée par le cancer et de trouver des moyens d’atténuer ces souffrances. Fondé sur des entretiens menés dans les hôpitaux avec des patientes et survivantes atteintes d’un cancer du col de l’utérus et du sein, cet article explore comment le cancer est souvent vécu par les femmes comme une souffrance biologique, sociale et spirituelle qui ne peut être soignée que lorsque des modalités biomédicales de traitement sont utilisées conjointement avec des modalités religieuses de guérison