SARS-CoV-2 Transmission Risk in the School Environment: a pilot case-ascertained prospective study to inform future school-based surveillance.

BACKGROUND: There is no current active or passive disease surveillance programme focused on schools in South Africa. As such the country is missing an opportunity to rapidly and effectively flag and address pathogen outbreaks, for example SARS-CoV-2, in a key closed setting. Furthermore, the role of school transmission in the spread of the SARS-CoV-2 virus within communities is uncertain.  Objective. This pilot study, conducted during March 2022 in Cape Town, aimed to indicate the feasibility of conducting intense active contact-tracing in a school environment prior to a large national study to compare school versus community SARS-CoV-2 transmission risk.  Methods. We conducted a pilot school-level case-ascertained prospective study with a component of enhanced surveillance. Following study initiation, the first learner at a participating school who tested SARS-CoV-2 positive (via Polymerase Chain Reaction (PCR) or a Rapid Antigen Test (RAT)) was invited to join the study as the index case and all their school-based close contacts were followed up telephonically, monitored for symptoms for 14 days, and tested using a PCR if any symptoms were reported.  Results. On 8th March 2022, a student with RAT laboratory-confirmed COVID-19 was identified and they and their guardian consented to participate as the index case. Of the 11 eligible close contacts, six provided consent/assent and completed symptom monitoring calls until the end of the 14-day study period. The Secondary Attack Rate (SAR) was 2/11 (18.18%) of all close contacts who were at risk of infection, 2/4 (50.0%) of all those close contacts who developed symptoms, and 2/4 (50.0%) of all those close contacts who developed symptoms and were tested for SARS-CoV-2. During the same period, the school reported that nine of the 926 learner body tested COVID-19 positive (0.97%). Total hours spent conducting monitoring for 6 learners was 27 hours, with each learner requiring approximately 4.5 hours of contact time during the study period.  Conclusion. This is the first South African school-based COVID-19 transmission study, the results of which can inform national discussions regarding the role of schools and school-based active and passive surveillance in pathogen prevention and control.

Brain-Specific Relative Biological Effectiveness of Protons Based on Long-term Outcome of Patients With Nasopharyngeal Carcinoma.

PURPOSE: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points. RESULTS: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18. CONCLUSIONS: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings.

Clinical management of COVID-19: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has presented clinicians with an enormous challenge in managing a respiratory virus that is not only capable of causing severe pneumonia and acute respiratory distress syndrome, but also multisystem disease. The extraordinary pace of clinical research, and particularly the surge in adaptive trials of new and repurposed treatments, have provided rapid answers to questions of whether such treatments work, and has resulted in corticosteroids taking centre stage in the management of hospitalised patients requiring oxygen support. Some treatment modalities, such as the role of anticoagulation to prevent and treat potential thromboembolic complications, remain controversial, as does the use of high-level oxygen support, outside of an intensive care unit setting. In this paper, we describe the clinical management of COVID-19 patients admitted to Groote Schuur Hospital, a major tertiary level hospital at the epicentre of South Africa's SARS-CoV-2 epidemic during its first 4 months.

Correction to: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.

Histone demethylase JARID1B/KDM5B promotes aggressiveness of non-small cell lung cancer and serves as a good prognostic predictor.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. Recently, epigenetic dysregulation has been known to promote tumor progression and therefore may be a therapeutic target for anticancer therapy. JARID1B, a member of histone demethylases, has been found to be related to tumorigenesis in certain kinds of cancers. However, its biological roles in non-small cell lung cancer (NSCLC) remain largely unclear. METHODS: We firstly examined the expression of JARID1B in surgical specimens and six NSCLC cell lines. Then, we evaluated the relationship between JARID1B expression and clinicopathologic parameters in 72 NSCLC patients, thereby established its prognostic importance. We subsequently studied the functional roles of JARID1B in tumorigenesis to verify its clinicopathologic significance. RESULTS: Our results showed that JARID1B was overexpressed in NSCLC cells and JARID1B overexpression was associated with tumor size, lymph node metastasis, advanced stages, and poor overall survival in NSCLC patients. JARID1B overexpression resulted in increased cell proliferation and formation of tumorspheres and correlated positively with the expression of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) markers, while the c-Met signaling pathway was actively involved. It also correlated with the strength of resistance to cisplatin and doxorubicin. On the contrary, downregulation of JARID1B expression by applying shRNA or JARID1B inhibitor PBIT reversed these phenomena. CONCLUSIONS: JARID1B worsens prognosis of NSCLC patients by promotion of tumor aggressiveness through multiple biological facets which were associated with activation of the c-Met signaling, and can be a novel prognostic biomarker and therapeutic target for NSCLC.

4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway.

Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P=0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy.

Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association.

This corrects the article DOI: 10.1038/onc.2015.397.

Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association.

Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.

EURO-MUSCULUS/USPRM. Basic Scanning Protocols for Ankle and foot.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned ankle/foot structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

EURO-MUSCULUS/USPRM. Basic scanning protocols for knee.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned knee structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

EURO-MUSCULUS/USPRM. Basic scanning protocols for hip.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned hip structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

EURO-MUSCULUS/USPRM Basic Scanning Protocols for shoulder.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned shoulder structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

EURO-MUSCULUS/USPRM Basic Scanning Protocols for elbow.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned elbow structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

EURO-MUSCULUS/USPRM Basic Scanning Protocols for wrist and hand.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned wrist/hand structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

The alanine detector in BNCT dosimetry: dose response in thermal and epithermal neutron fields.

PURPOSE: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. METHODS: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a (60)Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model. RESULTS: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. CONCLUSIONS: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.

Involvement of two distinct signalling pathways in IGF-1-mediated central control of hypotensive effects in normotensive and hypertensive rats.

AIMS: Insulin-like growth factor-1 (IGF-1) is abundantly expressed in the nucleus tractus solitarii (NTS). In a previous study, we revealed that the induction of nitric oxide (NO) production in the NTS reduces blood pressure (BP). It is well known that both acute administration and chronic administration of IGF-I reduce BP. The aim of this study was to evaluate the short-term hypotensive effect of IGF-1 in the NTS and to delineate the underlying molecular mechanisms of IGF-1 in the NTS of normotensive WKY rats and spontaneously hypertensive rats (SHRs). METHOD: Microinjections of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the MAP kinase-ERK kinase (MEK) inhibitor PD98059 into the NTS in WKY rats and SHRs were used to study the involvement of IGF-1-induced depressor effects. RESULT: An IGF-1 (7.7 pmol) injection into the NTS resulted in a significant decrease in BP and HR in WKY rats and SHRs. Immunoblotting and immunohistochemical analysis showed that the microinjection of LY294002 (0.6 pmol) or PD98059 (3.0 pmol) into the NTS attenuated the IGF-1-induced depressor effects and Akt or ERK phosphorylation in WKY rats. An attenuation effect of LY294002, but not PD98059, was found in the SHRs. However, the mRNA and protein expression levels of the IGF-1R showed no significant differences in the NTS of the WKY rats and the SHRs. CONCLUSION: These results suggest that distinct Akt and ERK signalling pathways mediated the IGF-1 control of the central depressor effects in WKY rats and SHRs. ERK signalling defects may be associated with the development of hypertension.

MTAP is an independent prognosis marker and the concordant loss of MTAP and p16 expression predicts short survival in non-small cell lung cancer patients.

OBJECTIVES: Methylthioadenosine phosphorylase (MTAP), a ubiquitously expressed protein, plays important roles in purine biosynthesis. Locating near to each other on chromosome 9p21-22, codeletion of the MTAP and p16(Ink4A) genes have been reported in non-small cell lung cancer (NSCLC). The aim of this study is to determine the respective prognostic value of MTAP and p16 by considering their correlation in NSCLC patients. MATERIALS AND METHODS: We analyzed MTAP and p16 protein expression by immunohistochemical staining on 99 NSCLC tissue microarray samples. The association between MTAP and p16 expression levels and prognosis were analyzed using the Kaplan-Meier method and Cox proportional hazards model for prognosis. RESULTS: Patients with a low MTAP expression level had poor overall survival (P = 0.010) and disease-free survival (P = 0.002). Low p16 expression indicated a trend toward poor overall survival (P = 0.138) and disease-free survival (P = 0.199). There was a significant positive correlation between MTAP and p16 expression levels (Spearman's ρ = 0.402, P < 0.001). By multivariate analyses, the MTAP expression level retained its independent prognostic power and p16 expression loss of the correlation with prognosis. Concordant loss of MTAP and p16 expression was observed in 24 out of 99 patients (24.2%). Patients with concordant loss of MTAP and p16 expression had the worst prognosis compared to patients with high expression of both markers. CONCLUSION: MTAP expression is an independent prognostic factor and has greater prognostic significance than p16 expression in NSCLC. Concordant loss of MTAP and p16 expression indicates poor outcomes in lung cancer patients.

MicroRNA-18a is elevated in prostate cancer and promotes tumorigenesis through suppressing STK4 in vitro and in vivo.

MicroRNAs (miRNAs) comprise a class of short, non-coding RNAs that regulate protein synthesis through posttranscriptional modifications. In this study, we found significant upregulation of miR-18a in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. MiRNAs can be separated into two groups based on whether they regulate tumor suppressors or oncogenes. In our previous study, we found that miR-18a, which belongs to the miR17-92 cluster, is upregulated in prostate cancer; the objective of this study was to investigate the associated regulatory mechanisms. We found that miR-18a is upregulated in clinical tumor specimens and cancer cell lines. Our bioinformatics analysis showed that the serine/threonine-protein kinase 4 (STK4) 3' untranslated region contains a highly conserved binding site for the miR-18a seed region. Luciferase reporter assays were performed to indicate that STK4 is a direct target of miR-18a. Interestingly, miR-18a knockdown decreased cell growth in prostate cancer cells and significantly decreased prostate tumor growth in in vivo nude mice experiments through STK4-mediated dephosphorylation of AKT and thereby inducing apoptosis. Our results suggest that miR-18a acts as an oncomiR targeting STK4 in prostate cancer, and inhibition of miR-18a expression may offer therapeutically beneficial option for prostate cancer treatment.

Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78.

Lung cancer is the leading cause of cancer deaths and is the most occurring malignancy worldwide. Unraveling the molecular mechanisms involved in lung tumorigenesis will greatly improve therapy. During early tumorigenesis, rapid proliferating tumor cells require increased activity of endoplasmic reticulum (ER) for protein synthesis, folding and secretion, thereby are subjected to ER stress. Ribosome-binding protein 1 (RRBP1) was originally identified as a ribosome-binding protein located on the rough ER and associated with unfolding protein response (UPR). In this report, we investigated the role of RRBP1 in lung cancer. RRBP1 was highly expressed in lung cancer tissue, as compared with adjacent normal tissues as assessed by immunohistochemistry (IHC) using lung cancer tissue array (n=87). Knockdown of RRBP1 by short-hairpin RNAs caused ER stress and significantly reduced cell viability and tumorigenicity. This effect was associated with a significant reduction in the expression of glucose-regulated protein 78 (GRP78). UPR regulator GRP78, an anti-apoptotic protein that is widely upregulated in cancer, has a critical role in chemotherapy resistance in some cancers. According to our results, cells with a higher level of RRBP1 were more resistant to ER stress. Ectopic expression of RRBP1 alleviated apoptosis that was induced by the ER-stress agent tunicamycin, 2-deoxy-D-glucose (2DG) or doxorubicin via enhancing GRP78 protein expression. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies using the database GSE10072. Our results also indicated that RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and GRP78. Taken together, RRBP1 could alleviate ER stress and help cancer cell survive. RRBP1 is critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.