PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability

Mutations in the phosphatase and tensin homolog (PTEN) gene leading to PTEN protein deletion and subsequent activation of the PI3K/Akt signaling pathway are common in cancer. Here we show that PTEN inactivation in human T cell acute lymphoblastic leukemia (T-ALL) cells is not always synonymous with PTEN gene lesions and diminished protein expression. Samples taken from patients with T-ALL at the time of diagnosis very frequently showed constitutive hyperactivation of the PI3K/Akt pathway. In contrast to immortalized cell lines, most primary T-ALL cells did not harbor PTEN gene alterations, displayed normal PTEN mRNA levels, and expressed higher PTEN protein levels than normal T cell precursors. However, PTEN overexpression was associated with decreased PTEN lipid phosphatase activity, resulting from casein kinase 2 (CK2) overexpression and hyperactivation. In addition, T-ALL cells had constitutively high levels of ROS, which can also downmodulate PTEN activity. Accordingly, both CK2 inhibitors and ROS scavengers restored PTEN activity and impaired PI3K/Akt signaling in T-ALL cells. Strikingly, inhibition of PI3K and/or CK2 promoted T-ALL cell death without affecting normal T cell precursors. Overall, our data indicate that T-ALL cells inactivate PTEN mostly in a nondeletional, posttranslational manner. Pharmacological manipulation of these mechanisms may open new avenues for T-ALL treatment.     

Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: a simple and rapid one-step method.

Bile acids play a pivotal role in the metabolism of cholesterol and lipids. Their blood concentrations are important prognostic and diagnostic indicators of hepatobiliary and intestinal dysfunction. This class of molecules comprises a heterogeneous group of compounds with a common cholesterol scaffold. Recently, the introduction of liquid chromatography coupled to tandem mass spectrometry methods has revealed an innovative path in the quantisation of specific bile acids in biological specimens. A robust and sensitive method has been developed based on high performance liquid chromatography separation coupled to an electrospray triple-quadrupole mass spectrometer. Human plasma samples were analysed on a C18 reverse-phase column. The elution profiles were monitored in multiple reaction-monitoring mode, quantifying and identifying each analyte by its own unique precursor to product patterns. A linear correlation over a broad range of bile acid concentrations (0.1-100 microM) was observed. The average recovery period for all of the analysed bile acids was 98 +/- 3%. Intra-day and inter-day precision averages were 2% and 5.4%, respectively. The determination was achieved within a single chromatographic run for all unconjugated, glycine- and taurine-conjugated isomeric forms of bile acids. As a proof of principle this method has been validated on a small subset of cholestatic patients (n = 7) and compared to appropriate clinical controls (n = 10). Based upon our encouraging experimental results, the described HPLC separation coupled to tandem mass spectrometry method for the analysis of bile acids in biological samples is deemed a robust and accurate procedure. Consequently, we propose this technique as a suitable candidate method for the identification and quantitation of bile acids in routine analysis.     

Efficacy of sertraline in a patient with Neuro-Beçhet’s disease

Behçet’s disease (BD) is a heterogeneous multisystem inflammatory disorder of unknown etiology, of which the involvement of the central nervous system is a serious manifestation (Neuro-Behçet’s syndrome, NBS). We report a 65-year-old patient who presented with a progressive cognitive impairment and behavioral disturbances (depression and apathy). He fulfilled the International Study Group criteria for BD. Treatment with sertraline was then commenced with an objective improvement of his cognitive and behavioral status. The current report describes a patient with an extensive history of NBS (almost 20 years) and a possible therapeutic option for behavioral impairment.     

Parry Romberg Syndrome associated with chronic facial pain

Parry Romberg Syndrome (PRS) is a rare condition of unknown cause and pathophysiology. It is characterized by progressive facial hemiatrophy, and neurological abnormalities are found in 20% of cases. We describe a 50-year-old woman with PRS and severe neurological involvement (lateralised epileptic seizure activity and facial pain refractory to medication). Pain intensity and frequency was reduced and control of epileptic crises was improved using levetiracetam as an additional therapy. In previous published cases associated with facial pain, the most frequent diagnoses were migraine and trigeminal neuralgia. Our findings suggest that in this patient PRS-related persistent pain has peculiar features possibly attributed to the underlying musculoskeletal abnormalities.     

Exploring the effectiveness of an Internet-based program for reducing caregiver distress using the iCare Stress Management e-Training Program

Objective: Determine if the online iCare Stress Management e-Training Program reduces stress, bother, depression, and poor life quality for dementia family caregivers (CGs).

Method: CGs (N = 150) were randomly assigned to the iCare Condition (ICC) or to the Education/Information-Only Condition (EOC) for a 3-month period. Change in self-report measures of stress (PSS) (primary outcome), caregiver bother(RMBPC), depression (CES-D), and quality of life (PQOL) (secondary outcomes) was determined, along with usage of new information in one's own caregiving.

Results: A mixed ANOVA revealed that change in perceived stress was significant for the ICC but not the EOC (p = .017). Changes in the other measures were not significant. More caregivers in the ICC used the materials in their own caregiving situation than those in the EOC. Roughly one-third of the caregivers enrolled in the study dropped prior to completion.

Conclusion: Results are promising, but the high dropout is a concern. Future efforts to improve dropout rate and increase participant engagement are warranted. To our knowledge, this is the first attempt to present an evidence-based intervention for CGs via the Internet.     

D-π-A-Type Pyrazolo[1,5-a]pyrimidine-Based Hole-Transporting Materials for Perovskite Solar Cells: Effect of the Functionalization Position

Donor–acceptor (D–A) small molecules are regarded as promising hole-transporting materials for perovskite solar cells (PSCs) due to their tunable optoelectronic properties. This paper reports the design, synthesis and characterization of three novel isomeric D-π-A small molecules PY1, PY2 and PY3. The chemical structures of the molecules consist of a pyrazolo[1,5-a]pyrimidine acceptor core functionalized with one 3,6-bis(4,4′-dimethoxydiphenylamino)carbazole (3,6-CzDMPA) donor moiety via a phenyl π-spacer at the 3, 5 and 7 positions, respectively. The isolated compounds possess suitable energy levels, sufficient thermal stability (T_d > 400 °C), molecular glass behavior with T_g values in the range of 127–136 °C slightly higher than that of the reference material Spiro-OMeTAD (126 °C) and acceptable hydrophobicity. Undoped PY1 demonstrates the highest hole mobility (3 × 10⁻⁶ cm² V⁻¹ s⁻¹) compared to PY2 and PY3 (1.3 × 10⁻⁶ cm² V⁻¹ s⁻¹). The whole isomers were incorporated as doped HTMs in planar n-i-p PSCs based on double cation perovskite FA_0.85Cs_0.15Pb(I_0.85Br_0.15)₃. The non-optimized device fabricated using PY1 exhibited a power conversion efficiency (PCE) of 12.41%, similar to that obtained using the reference, Spiro-OMeTAD, which demonstrated a maximum PCE of 12.58% under the same conditions. The PY2 and PY3 materials demonstrated slightly lower performance in device configuration, with relatively moderate PCEs of 10.21% and 10.82%, respectively, and slight hysteresis behavior (−0.01 and 0.02). The preliminary stability testing of PSCs is also described. The PY1-based device exhibited better stability than the device using Spiro-OMeTAD, which could be related to its slightly superior hydrophobic character preventing water diffusion into the perovskite layer.     

Emergence of a Reassortant 2.3.4.4b Highly Pathogenic H5N1 Avian Influenza Virus Containing H9N2 PA Gene in Burkina Faso,West Africa,in 2021

Since 2006, the poultry population in Burkina Faso has been seriously hit by different waves of Highly Pathogenic Avian Influenza (HPAI) H5N1 epizootics. In December 2021, three distinct regions of Burkina Faso, namely, Gomboussougou, Bonyollo, and Koubri, detected HPAI H5N1 viruses in poultry. Whole genome characterization and statistical phylogenetic approaches were applied to shed light on the potential origin of these viruses and estimate the time of virus emergence. Our results revealed that the HPAI H5N1 viruses reported in the three affected regions of Burkina Faso cluster together within clade 2.3.4.4b, and are closely related to HPAI H5N1 viruses identified in Nigeria and Niger in the period 2021–2022, except for the PA gene, which clusters with H9N2 viruses of the zoonotic G1 lineage collected in West Africa between 2017 and 2020. These reassortant viruses possess several mutations that may be associated with an increased zoonotic potential. Although it is difficult to ascertain where and when the reassortment event occurred, the emergence of a H5N1/H9N2 reassortant virus in a vulnerable region, such as West Africa, raises concerns about its possible impact on animal and human health. These findings also highlight the risk that West Africa may become a new hotspot for the emergence of new genotypes of HPAI viruses.     

Impact of COVID-19 Lockdown on Food Consumption and Behavior in France (COVISTRESS Study)

The COVID-19 pandemic and subsequent lockdowns modified work environments, lifestyles, and food consumption. Eating habits and mood changes in a French population during the first lockdown were examined using an online self-reported questionnaire with REDCap software through the COVISTRESS.ORG website. In 671 French participants, the main changes during lockdown were increased stress levels (64 [23; 86] vs. 3 [0; 18]) and sedentary behavior (7 [4; 9] vs. 5 [3; 8] hours per day), a deterioration in sleep quality (50 [27; 83] vs. 70 [48; 94]) and mood (50 [30; 76] vs. 78 [50; 92]), and less physical activity (2.0 [0.5; 5.0] vs. 3.5 [2.0; 6.0]). Mood was modified, with more anger (56 [39; 76] vs. 31 [16; 50]), more sadness (50 [34; 72] vs. 28 [16; 50]), more agitation (50 [25; 66] vs. 43 [20; 50]), and more boredom (32 [7; 60] vs. 14 [3; 29]). A total of 25% of the participants increased their consumption of alcoholic beverages, 29% their consumption of sugary foods, and 26% their consumption of cocktail snacks. A multiple-correspondence analysis highlights four different profiles according to changes in eating habits, food consumption, lifestyle, and mood. In conclusion, eating habits and lifestyle changes during lockdown periods should be carefully monitored to promote healthy behaviors.     

The Impact of Job-Demand-Control-Support on Leptin and Ghrelin as Biomarkers of Stress in Emergency Healthcare Workers

Despite the available literature on the consequences of night shiftwork on stress and food intake, its impact on leptin and ghrelin has never been studied. We previously demonstrated that leptin and ghrelin were biomarkers related to stress, and acute stress-induced a decrease in leptin levels and an increase in ghrelin levels. We performed a prospective observational study to assess the influence of night work, nutrition, and stress on the levels of ghrelin and leptin among emergency healthcare workers (HCWs). We took salivary samples at the beginning of a day shift and/or at the end of a night shift. We also monitored stress using the job demand-control-support model of Karasek. We recorded 24-h food intake during the day shift and the consecutive night shift and during night work and the day before. We included 161 emergency HCWs. Emergency HCWs had a tendency for decreased levels of leptin following the night shift compared to before the dayshift (p = 0.067). Furthermore, the main factors explaining the decrease in leptin levels were an increase in job-demand (coefficient −54.1, 95 CI −99.0 to −0.92) and a decrease in job control (−24.9, −49.5 to −0.29). Despite no significant changes in ghrelin levels between shifts, social support was the main factor explaining the increase in ghrelin (6.12, 0.74 to 11.5). Food intake (kcal) also had a negative impact on leptin levels, in addition to age. Ghrelin levels also decreased with body mass index, while age had the opposite effect. In conclusion, we confirmed that ghrelin and leptin as biomarkers of stress were directly linked to the job demand-control-support model of Karasek, when the main cofounders were considered.