Harnessing the p53-PUMA Axis to Overcome DNA Damage Resistance in Renal Cell Carcinoma

Resistance to DNA damage–induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC). This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage–induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA). We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF) but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage–induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.     

Atrial electromechanical coupling intervals in pregnant subjects

Atrial fibrillation (AF), which is the most common cardiac arrhythmia, may cause serious symptoms and impair quality of life.1 The development of AF is associated with many risk factors, including age, male gender, hypertension, heart failure, valvular disease, diabetes mellitus (DM) and left atrial (LA) enlargement.2-4 Electrical and/or mechanical remodelling of the atria is thought to be a pathophysiological characteristic of AF.5The pregnant state may be pro-dysrhythmic. This is related to the cardiovascular, hormonal, haemodynamic and autonomic changes during healthy pregnancy. Levels of oestrogen and β-human chorionic gonadotropin increase dramatically. Haemodynamic changes include an increase in circulating blood volume, which increases cardiac output. This results in myocardial stretch and an increase in cardiac end-diastolic volume. High plasma catecholamine concentrations and adrenergic receptor sensitivity increase sympathetic tone. All these changes in pregnant women may make them more prone to dysrhythmogenesis.6Most pregnant women complain of palpitations, dizziness and even syncope, but these symptoms are rarely associated with cardiac dysrhythmias. AF is the most common clinically significant cardiac arrhythmia in the general population but it is rarely seen in pregnant women. When it occurs, it can represent a benign, self-limited lone episode of AF or may be secondary to congenital or rheumatic valvular disease, hypertrophic cardiomyopathy, thyroid disease, or pre-excitation syndrome.Two simple electrocardiogram (ECG) markers, namely maximum P-wave duration (Pmax) and P-wave dispersion (PD), have been used to evaluate intra- and inter-atrial conduction times and the inhomogeneous propagation of sinus impulses, which are well-known electrophysiological characteristics of the atrium prone to fibrillation.7,8 Prolonged Pmax and PD have been reported to represent an increased risk for AF in patients with no underlying heart disease.7,8 Besides, evidence from laboratory and epidemiological research suggests that systemic inflammation may play a role in AF aetiology.9 It has also been demonstrated that atrial electromechanical coupling, measured by tissue Doppler imaging (TDI), as significantly longer in patients with paroxysmal AF than in control groups.10,11To our knowledge, no study evaluating PD and atrial electromechanical coupling has been investigated in pregnant subjects without additional systemic disease. Therefore, in this study we aimed to examine atrial electromechanical coupling and PD, reflecting inter-atrial conduction times in pregnant subjects.     

A multi-institutional comparison of mitoxantrone,etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.     

Biochemical and pathologic factors affecting technetium-99m-methoxyisobutylisonitrile imaging results in patients with primary hyperparathyroidism

Objective

Technetium 99 m methoxyisobutylisonitrile (Tc-99m MIBI) scintigraphy represents the most commonly utilized imaging modality for the detection of the diseased gland in patients with primary hyperparathyroidism (PHPT). In this study, we aimed to identify potential biological factors with an impact on MIBI sensitivity.

Methods

A total of 147 patients with surgically confirmed parathyroid adenomas were assessed retrospectively. Data including medical history, biochemical and hormonal measurements, cervical US, Tc-99m MIBI scans as well as pathology reports were retrieved and recorded.

Results

Of the 147 patients, there were a total of 77, 39, and 31 cases with a positive, negative, and suspicious parathyroid adenoma on Tc-99m MIBI scan, respectively. Serum calcium (Ca), parathyroid hormone (PTH) and 25 (OH) D levels were comparable among MIBI positive and negative patients [Ca: 11.5?±?0.9 vs 11.3?±?0.9 mg/dL (P?=?0.42); PTH: 216 (146–347) vs 194 (140–317) pg/mL (P?=?0.45); 25(OH)D: 8.4 (5.7–18.2) vs 10.0 (4.7–23.3) ng/mL (P?=?0.64), respectively]. P-glycoprotein (P-gp) staining was negative in both groups. Also, pathological examination of tissue preparations revealed no difference in terms of the volume of the adenomas, incidence of cystic adenomas, cell-type dominance (oxyphilic cell), percent fat, and Ki-67 ratio in MIBI positive and negative groups. The rate of hyalinization was 13% in MIBI positive and 28% in MIBI negative subjects, the difference being statistically significant (P?=?0.04).

Conclusion

Presence of hyalinization in parathyroid adenomas was found to be negatively correlated with MIBI scan results.

     

Serum osteocalcin levels in hyperthyroidism before and after antithyroid therapy

Hyperthyroidism is characterized by accelerated bone turnover, caused from direct stimulation of bone cells by increased thyroid hormones. In this study, we aimed to investigate serum osteocalcin levels as a bone formation marker, before antithyroid (propylthiouracil) therapy at hyperthyroid stage and after antithyroid therapy at euthyroid stage of the patients. Twenty four hyperthyroid patients (18 females, 6 males) and 20 (13 females, 7 males) healthy controls were included into this study. Blood and urine samples were taken before medical treatment at hyperthyroid state, and after the antithyroid therapy until the patients reached the euthyroid state. Serum alkaline phosphatase, osteocalcin, calcium, phosphorus, Free T3, Free T4, TSH and urine calcium/creatinine levels were assessed. We found a significant decrease in serum osteocalcin (p=0.006), urinary calcium/creatinine (p=0.004), and serum phosphorus (p=0.038) levels in euthyroid state in comparison to hyperthyroid state. The increases in serum bone formation marker osteocalcin and bone resorption marker urinary calcium/creatinine levels in hyperthyroid state compared to euthyroid state in our study confirmed that hyperthyroid patients have high bone turnover. We conclude that, hyperthyroid patients has high bone turnover of formation and resorption even after attainment of euthyroidism. Osteocalcin and urine calcium/creatinine are sensitive markers in documenting bone remodeling during treatment of hyperthyroidism.     

Diode laser-assisted endoscopic dacryocystorhinostomy: a comparison of three different combinations of adjunctive procedures

Chronic dacryocystitis is a frequently encountered condition which can be corrected by dacryocystorhinostomy. Today, the diode laser is increasingly put to use in such corrective operations. This study aims to answer the questions of which adjunctive procedures and which combinations of such procedures are necessary and effective in securing more successful outcomes in diode laser dacryocystorhinostomy. This prospective randomized study included eighty patients (13 male, 67 female) who underwent dacryocystorhinostomy in our hospital during the 2 year period of January 2009–January 2011. The patients were selected consecutively and were randomly allocated to three groups. Group 1 (30): diode laser + mitomycin C + silicone intubation; Group 2 (27): diode laser + silicone intubation; Group 3 (23): diode laser + mitomycin C. All patients were evaluated postoperatively on day 1, week 1, and on the 1st, 3rd, 6th, 12th, 18th, and 24th months. The postoperative evaluation consisted of preoperative and postoperative ostium measurements, recording postoperative complications, and calculating and comparing success rates and operative times. The mean ages of the patients were 63.4 for Group 1, 60.7 for Group 2, and 61.8 for Group 3. No statistically significant difference was found among the groups regarding pre- and postoperative ostium measurements. The success rates were 84.3, 80, and 76.9 % for Groups 1, 2, and 3, respectively. Complications noted in Group 1 were restenosis (3), premature silicone tube loss (1), development of granulation tissue (3), synechia (2), infection (2), and hemorrhage (3). Those for Group 2 were restenosis (5), premature tube loss (2), granulation (8), synechia (6), infection (3), and hemorrhage (4). Group 3 had 6 cases with stenosis, 5 with granulation, 3 with infection, 6 with synechia, and 5 with hemorrhage. The operative times of the groups were 25.5, 15.3, and 18.1 min, respectively, for Group 1, 2, and 3. All three groups had statistically significant differences regarding the duration of surgery, with p < 0.001, p < 0.001, and p = 0.002 for Group 1 and 2, Group 1 and 3, and Group 2 and 3, respectively. Our study showed that when diode laser DCR was combined with bicanalicular silicone intubation and intraoperative mitomycin C application, those adjunctive procedures, while increasing operative time, enhanced the success rate and diminished complications as compared to diode laser plus intubation and/or diode laser plus mitomycin C.     

COVID-19-related oral mucosa lesions among confirmed SARS-CoV-2 patients: a systematic review

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19), which manifests as a flu-like respiratory infection affecting multiple organ systems, including the gastrointestinal system, central nervous system, cardiovascular system, skin, and mucosa. In this review, we investigated the literature on specific manifestations of COVID-19 in the oral mucosa. An online literature search in PubMed, Scopus, Google Scholar, and Medline was conducted to retrieve relevant studies on confirmed COVID-19 patients with oral mucosa findings published between December 31, 2019, and April 07, 2021. After an independent review by two authors, 39 articles considering 59 laboratory-confirmed cases of SARS-CoV-2 infection were included in the final analysis. The most common finding, reported in 29 patients (43.9%), was Kawasaki-like syndrome. In addition, oral ulcers including aphthous, hemorrhagic, and necrotic ulcers were reported in 24 patients (36.3%). Other lesions reported included pustules, macules, bullae, maculopapular enanthema, and erythema multiforme-like lesions. Concomitant skin lesions were present in 60.6% of patients. Fever was reported in 86.2% of patients. Forty-eight patients (76.1%) were hospitalized. Loss of taste and smell was present in 30.8% of the patients. A comprehensive understanding of the dermatologic manifestations of COVID-19 can improve and facilitate patient management and referrals.     

The effect of maxillary sinus surgery on its development

CONCLUSION: The study showed that surgery in the maxillary sinus can affect its development. OBJECTIVE: To quantitatively evaluate the long-term impact of sinus surgery on its development in the rabbit. MATERIALS AND METHODS: This was an experimental study performed at an academic tertiary medical center using 20 4-week-old New Zealand white rabbits. The rabbits underwent unilateral right maxillary sinus surgery. The contralateral maxillary sinus used as a control did not undergo the operation. The maxillary sinus ostium was enlarged on the operated side. Volumetric analysis of the maxillary sinus was performed 1 year post-surgery. The maxillary sinus volumes of both sides were calculated using Multidedector CT and the volumetric measurements of the operated side were compared with the non-operated side. RESULTS: Maxillary sinus development was significantly reduced on the surgical side. Maxillary sinus growth on the surgical side was determined as 87% compared with the non-surgical side.     

Evaluation of the current post‐transplantation Human Leukocyte Antigen antibody screening in pediatric renal transplant recipients

The necessity of post‐transplant monitoring for donor‐specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post‐transplantation donor‐specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post‐transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post‐transplant DSA on clinical outcome, including antibody‐mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA‐positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post‐transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.