HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8⁺ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.     

Unexpected recovery from longterm renal failure in severe diffuse proliferative lupus nephritis

ABSTRACT: BACKGROUND: Severe renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated. CASE PRESENTATION: We report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of (SLE and the patient was immediately treated with methylprednisolone, cyclophoshamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continous immunosuppressive therapy with Mycophenolate mofetil (MMF). CONCLUSION: Despite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparentlyhas a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.     

The Suitability of Questionnaires for Exploring Relations of Dietary Behavior and Tooth Wear

Tooth wear is a relevant oral health problem, especially at a young age. Although ongoing acid exposures may contribute to tooth wear, the role of acidic dietary components in this context remains unclear. To date, in tooth wear studies, dietary behavior has been assessed using traditional questionnaires, but the suitability of this approach has not been investigated so far. In our longitudinal study, we followed 91 participants (21.0 ± 2.2 years) over a period of 1 year (373 ± 19 days) and monitored tooth wear with an intraoral scanner. At baseline (T0) and at the end (T1), we assessed dietary behavior with questionnaires asking about the consumption frequencies of acidic dietary components and the acid taste preferences. Complete data were available from 80 subjects. The consumption frequencies of T0 and T1 correlated weakly to moderately. Taste preferences seem to be a more consistent measure, but there was predominantly no significant correlation with the corresponding consumption frequencies. None of the dietary parameters showed a significant relation with tooth wear. The suitability of dietary questionnaires to assess tooth-relevant dietary behavior seems to be limited.     

Utilization of just-in-time training for nursing education using the LA Phonospirometry asthma tool

Objective: Just-in-time training (JITT) has been used to teach and re-teach known medical techniques, but has not been used to teach novel techniques. We aimed to assess the performance retention of JITT on a novel asthma exacerbation severity assessment technique known as Los Angeles (LA) Phonospirometry. Methods: This was a prospective cohort study using a convenience sample of pediatric emergency department registered nurses (RNs) who were asked to watch a brief instructional digital video on LA Phonospirometry, and then asked to practice the technique on a research assistant (RA). A checklist was used to evaluate proficiency with the primary outcome being the number correct on the checklist. The secondary outcome included whether or not they could identify a common error demonstrated by the RA. RNs were re-tested after 4–6 months to assess skill retention. Results: Forty RNs were enrolled in the study and six were lost to follow-up. The mean time from the first to second testing was 5.4 months ± 0.5 months. The mean score of the first part of the checklist on the initial testing was 4.6 ± 0.7 and on second testing was 3.8 ± 1.5 (p = 0.008). This represented a drop in scores and thus minimal knowledge decay of 18% (from 91% to 73%). The mean values for number of errors picked up for the first test and second test were 1.3 and 1.5, respectively (p = 0.2). Conclusions: JITT demonstrated feasibility as a rapid instructional tool for RNs, with a limited decay in cognitive knowledge surrounding the LA Phonospirometry technique.     

On the rise and fall of the apnea−hypopnea index: A historical review and critical appraisal

The publication of “The Sleep Apnea Syndromes” by Guilleminault et al. in the 1970s hallmarked the discovery of a new disease entity involving serious health consequences. Obstructive sleep apnea was shown to be the most important disorder among the sleep apnea syndromes (SAS). In the course of time, it was found that the prevalence of obstructive sleep apnea reached the proportions of a global epidemic, with a major impact on public health, safety and the economy. Early on, a metric was introduced to gauge the seriousness of obstructive sleep apnea, based on the objective measurement of respiratory events during nocturnal sleep. The apnea index and later on the apnea?hypopnea index, being the total count of overnight respiratory events divided by the total sleep time in hours, were embraced as principle measures to establish the diagnosis of obstructive sleep apnea and to rate its severity. The current review summarises the historical evolution of the apnea?hypopnea index, which has been subject to many changes, and has been criticised for not capturing relevant clinical features of obstructive sleep apnea. In fact, the application of the apnea?hypopnea index as a continuous exposure variable is based on assumptions that it represents a disease state of obstructive sleep apnea and that evocative clinical manifestations are invariably caused by obstructive sleep apnea if the apnea?hypopnea index is above diagnostic threshold. A critical appraisal of the extensive literature shows that both assumptions are invalid. This conclusion prompts a reconsideration of the role of the apnea?hypopnea index as the prime diagnostic metric of clinically relevant obstructive sleep apnea.