Annexin/S100A protein family regulation through p14ARF-p53 activation: A role in cell survival and predicting treatment outcomes in breast cancer

© 2017 Hatoum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The annexin family and S100A associated proteins are important regulators of diverse calcium- dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes

Two weeks delayed bleeding in blunt liver injury: case report and review of the literature

Most cases of blunt hepatic trauma are treated nowadays non-operatively. This type of conservative treatment has resulted in increased complication rate. Delayed complications occur in cases that didn't require surgical intervention during the first 24 hours. The most common late complication is hemorrhage. We report a case of two weeks delayed hemorrhage after blunt hepatic trauma in an adult. We describe the diagnostic procedures, the surgical treatment and review the relevant literature

The Influence of Decoys on the Noise and Dynamics of Gene Expression

Many transcription factors bind to DNA with a remarkable lack of specificity, so that regulatory binding sites compete with an enormous number of non-regulatory 'decoy' sites. For an auto-regulated gene, we show decoy sites decrease noise in the number of unbound proteins to a Poisson limit that results from binding and unbinding. This noise buffering is optimized for a given protein concentration when decoys have a 1/2 probability of being occupied. Decoys linearly increase the time to approach steady state and exponentially increase the time to switch epigenetically between bistable states.Comment: 8 pages, 4 figure

Non-Hodgkin's lymphoma in a woman with adult-onset Still's disease: a case report

INTRODUCTION: Adult onset Still's disease is a chronic multisystemic inflammatory disorder characterized by high spiking fever, polyarthralgia and rash. Lymphadenopathy is a prominent feature of adult onset Still's disease and is seen in about 65% of patients. Searching the medical literature using the MEDLINE database from January 1966 through November 2007 we could only find two reported cases of adult onset Still's disease that had progressed to lymphoma. CASE PRESENTATION: We describe a woman who was diagnosed with adult onset Still's disease and developed lymphoma 10 months after the onset of her symptoms. She initially presented with fever and arthritis of the knees, ankles and shoulders, along with a nonpruritic skin rash, myalgia and weight loss. On physical examination she was found to have several enlarged anterior cervical lymph nodes and left posterior auricular lymph nodes all of which were non-tender, immobile and rubbery. Excisional biopsy of the cervical lymph nodes was negative for malignancy. Bone marrow biopsy was also negative for malignancy. She was treated with prednisone. She remained in good health until she presented 10 months later with low back pain, dyspnea and weight loss. Work up revealed malignant lymphoma. She was treated with chemotherapy and was doing well until she presented with abdominal pain. Work up revealed a cirrhotic liver and ascites. She then passed away from hepatorenal syndrome 13 years after the diagnosis of lymphoma. To our knowledge, this is the third reported case of such an occurrence. CONCLUSION: Although the association between adult onset Still's disease and lymphoma has been rarely reported, careful screening for this malignancy in patients suspected to have adult onset Still's disease is warranted

Genetic liability to cannabis use disorder and COVID-19 hospitalization

BACKGROUND: Vulnerability to COVID-19 hospitalization has been linked to behavioral risk factors, including combustible psychoactive substance use (e.g., tobacco smoking). Paralleling the COVID-19 pandemic crisis have been increasingly permissive laws for recreational cannabis use. Cannabis use disorder (CUD) is a psychiatric disorder that is heritable and genetically correlated with respiratory disease, independent of tobacco smoking. We examined the genetic relationship between CUD and COVID-19 hospitalization. METHODS: We estimated the genetic correlation between CUD (case: RESULTS: Genetic vulnerability to COVID-19 was correlated with genetic liability to CUD ( CONCLUSIONS: Problematic cannabis use and vulnerability to serious COVID-19 complications share genetic underpinnings that are unique from common correlates. While CUD may plausibly contribute to severe COVID-19 presentations, causal inference models yielded no evidence of putative causation. Curbing excessive cannabis use may mitigate the impact of COVID-19

Association of Bovine Arch Anatomy With Incident Stroke After Transcatheter Aortic Valve Replacement

BACKGROUND: Acute ischemic stroke complicates 2 % to 3 % of transcatheter aortic valve replacements (TAVRs). This study aimed to identify the aortic anatomic correlates in patients after TAVR stroke. METHODS AND RESULTS: This is a single-center, retrospective study of patients who underwent TAVR at the Mayo Clinic between 2012 and 2022. The aortic arch morphology was determined via a manual review of the pre-TAVR computed tomography images. An a priori approach was used to select the covariates for the following: (1) the logistic regression model assessing the association between a bovine arch and periprocedural stroke (defined as stroke within 7 days after TAVR) and (2) the Cox proportional hazards regression model assessing the association between a bovine arch and long-term stroke after TAVR. A total of 2775 patients were included (59.6 % men, 97.8 % White race, mean ± SD age, 79.3 ± 8.4 years), of whom 495 (17.8 %) had a bovine arch morphology. Fifty-seven patients (1.7 %) experienced a periprocedural stroke. The incidence of acute stroke was significantly higher among patients with a bovine arch compared with those with a nonbovine arch (3.6% versus 1.7%; =0.01). After adjustment, a bovine arch was independently associated with increased periprocedural strokes (adjusted odds ratio, 2.16 [95 % CI, 1.22-3.83]). At a median follow-up of 2.7 years, the overall incidence of post-TAVR stroke was 6.0 % and was significantly higher in patients with a bovine arch even after adjusting for potential confounders (10.5 % versus 5.0 % adjusted hazard ratio, 2.11 [95 % CI, 1.51-2.93], \u3c 0.001). CONCLUSIONS: A bovine arch anatomy is associated with a significantly higher risk of periprocedural and long-term stroke after TAVR

Acute cholecystitis managed in a rural surgical department

ObjectivesTo define the outcome over a prolonged period of an unselected cohort of patients presenting with acute cholecystitis (AC) to a 560 bed rural hospital in Israel.Design, setting and participantsRetrospective case series analysed from a single referral centre between 2006 and 2015. Separated into Group 1 managed by emergent cholecystectomy, Group 2 treated with antibiotics and delayed cholecystectomy, Group 3 treated with percutaneous cholecystostomy (PC) and selected delayed cholecystectomy and Group 4 managed entirely conservatively with no subsequent cholecystectomy.Methods Assessment of complication rates: in-hospital and delayed cause-specific morbidity and mortality along with conversion rates and the risk of intraoperative stone spillage. Results Of 321 patients hospitalized for AC, there were 50 in Group 1, 68 in Group 2, 59 in Group 3 and 98 in Group 4. Group 3 were older with more comorbidities and when coming to surgery had more open conversions. Intraoperative stone spillage was more common in Groups 2 and 3. The length of hospital stay was greater for Groups 1 and 3. Of the Group 4 cases, 63.2 per cent remained asymptomatic over a median follow-up of 78 months. Of those with recurrent biliary symptoms, 58.3 per cent were ASA Grade III/IV with 25/36 late deaths 80 per cent of which were from non-biliary causes. ConclusionIn the management of AC, early cholecystectomy is favored with non-operative approaches like PC drainage or antibiotic treatment alone being reserved for frailer comorbid cases. The absolute need for subsequent cholecystectomy is not supported by this series and requires further investigation

Influence of real-world characteristics on outcomes for patients with methicillin-resistant Staphylococcal skin and soft tissue infections:a multi-country medical chart review in Europe

BACKGROUND: Patient-related (demographic/disease) and treatment-related (drug/clinician/hospital) characteristics were evaluated as potential predictors of healthcare resource use and opportunities for early switch (ES) from intravenous (IV)-to-oral methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotic therapy and early hospital discharge (ED). METHODS: This retrospective observational medical chart study analyzed patients (across 12 European countries) with microbiologically confirmed MRSA complicated skin and soft tissue infections (cSSTI), ≥3 days of IV anti-MRSA antibiotics during hospitalization (July 1, 2010-June 30, 2011), and discharged alive by July 31, 2011. Logistic/linear regression models evaluated characteristics potentially associated with actual resource use (length of IV therapy, length of hospital stay [LOS], IV-to-oral antibiotic switch), and ES and ED (using literature-based and expert-verified criteria) outcomes. RESULTS: 1542 patients (mean ± SD age 60.8 ± 16.5 years; 61.5% males) were assessed with 81.0% hospitalized for MRSA cSSTI as the primary reason. Several patient demographic, infection, complication, treatment, and hospital characteristics were predictive of length of IV therapy, LOS, IV-to-oral antibiotic switch, or ES and ED opportunities. Outcomes and ES and ED opportunities varied across countries. Length of IV therapy and LOS (r = 0.66, p < 0.0001) and eligibilities for ES and ED (r = 0.44, p < 0.0001) showed relatively strong correlations. IV-to-oral antibiotic switch patients had significantly shorter length of IV therapy (−5.19 days, p < 0.001) and non-significantly shorter LOS (−1.86 days, p > 0.05). Certain patient and treatment characteristics were associated with increased odds of ES (healthcare-associated/ hospital-acquired infection) and ED (patient living arrangements, healthcare-associated/ hospital-acquired infection, initiating MRSA-active treatment 1–2 days post cSSTI index date, existing ED protocol), while other factors decreased the odds of ES (no documented MRSA culture, ≥4 days from admission to cSSTI index date, IV-to-oral switch, IV line infection) and ED (dementia, no documented MRSA culture, initiating MRSA-active treatment ≥3 days post cSSTI index date, existing ES protocol). CONCLUSIONS: Practice patterns and opportunity for further ES and ED were affected by several infection, treatment, hospital, and geographical characteristics, which should be considered in identifying ES and ED opportunities and designing interventions for MRSA cSSTI to reduce IV days and LOS while maintaining the quality of care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2334-14-476) contains supplementary material, which is available to authorized users

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids \u27not as prescribed\u27. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (