ZBTB16: A new biomarker for primitive neuroectodermal tumor element / Ewing sarcoma

Primitive neuroectodermal tumor (PNET) traditionally encompasses two different classes of tumors with similar morphology - PNET of the peripheral nervous system (pPNET) and PNET of the central nervous system (cPNET). The latter also includes germ cell tumor-derived PNET (gPNET). There are currently no specific markers for gPNET. This study seeks to investigate the expression of ZBTB16 in PNET and other small round blue cell tumors as well as its potential diagnostic utility. Immunohistochemical expression of the ZBTB16 was studied in a total of 27 PNETs (12 pPNETs, 8 cPNETs, 3 primary testicular gPNETs, and 4 metastatic gPNETs) and 38 small round blue cell tumors. Positive expression for ZBTB16 was seen diffusely in 9/12 (75%), moderately in 2/12 (17%) and focally in 1/12 (8%) of pPNETs, diffusely in 3/7 (43%) and moderately in 4/7 (57%) of gPNETs, and diffusely in 2/8 (25%), moderately in 2/8 (25%) and focally in 4/8 (50%) of cPNETs. Whereas, all of the 38 non-PNET small round blue cell tumors were nonreactive. The results suggest that ZBTB16 is a highly sensitive and specific biomarker for both pPNET and gPNET/cPNET. ZBTB16 effectively differentiates PNETs from other small round blue cell tumor mimics, including the two most common germ cell tumor-derived somatic malignancies - rhabdomyosarcoma and nephroblastoma. Of note, compared to the expression of ZBTB16 in pPNET/Ewing sarcoma and gPNET, the expression of ZBTB16 in cPNET was more variable, which appears consistent with the heterogeneity of cPNET. The close proximity of ZBTB16 and FLI-1 genes on chromosome 11q may explain the overexpression of ZBTB16 in PNET, especially in pPNET with t(1122) translocation.     

Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Effectiveness of Influenza Vaccine in Hemodialyzed Patients: A Retrospective Study

Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza vaccination among hemodialysis (HD) patients. In the 2014–2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015–2016 by the hospital dialysis unit staff during an inpatient HD session (P <0.001). A trend toward fewer complications from influenza infection was observed in vaccinated patients. Among HD patients with diabetes (who comprised 56% of the study population), the incidence of influenza was 17% among nonvaccinated patients vs. 6.3% among those who were vaccinated (P =0.026). The inpatient vaccination policy resulted in a greater rate of vaccination. HD patients with diabetes benefit from influenza vaccination, with a significantly lower incidence of influenza infection.     

Gastrocnemius tightness: A population based observational study

BackgroundGastrocnemius tightness is believed to be associated with multiple musculoskeletal pathologies such as back pain, plantar fasciitis and metatarsalgia. Although surgical treatment of gastrocnemius tightness is gaining popularity the objective definition of a gastrocnemius contracture has not been determined. The aim of our study was therefore to quantify gastrocnemius tightness in a normal population.MethodsAdult participants with no obvious foot and ankle pathology were recruited. Gastrocnemius tightness was quantified using a weightbearing lunge test. Maximal ankle-foot dorsiflexion was measured on participants with the knee in full extension and flexed to 20° using a digital inclinometer. The ankle-foot dorsiflexion index or ADI (difference in ankle dorsiflexion with the knee extended and flexed) was calculated. The ADI values were plotted on a histogram to identify the distribution of values and were compared according to participant demographics.Results800 limbs from 400 participants were examined. There was a wide distribution of absolute values of maximal ankle-foot dorsiflexion ranging from 8 to 52°. The ADI ranged from 0 to19° and approximated to a normal distribution. The mean ADI was 6.04 ± 3.49° and was positively correlated with age (r = 0.132, P < 0.001) and negatively correlated with physical activity (r = ?0.88, P = 0.015).Conclusion(s)Our study is the first to quantify gastrocnemius tightness in a large healthy adult population with differences observed by age and physical activity. We have defined an easy and reproducible weightbearing test that can be used in both research and clinical settings. The majority of the population have some degree of gastrocnemius tightness and values of ADI greater than 13° (>2 SD of the mean), as measured by the lunge test, may be considered abnormal.     

Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).