Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

The number of gonococcal infections identified by the RENAGO network is increasing

Surveillance of sexually transmitted infections (STIs) in France is based mainly on laboratory reporting, as STIs are not among the diseases notified by physicians. The network RENAGO (Reseau National du Gonocoque) was set up in 1986 to monitor national t     

Determinants of Patient's Adherence to Hypertension Medications in a Rural Population of Kancheepuram District in Tamil Nadu,South India

Context:

Non-communicable diseases, no longer a disease of the rich, impose a great threat in the developing nations due to demographic and epidemiological transition. This increasing burden of non-communicable diseases and their risk factors is worrisome. Adherence to hypertension (HT) medication is very important for improving the quality of life and preventing complications of HT.

Aim:

To study the factors determining adherence to HT medication.

Settings and Design:

A community-based cross-sectional study was conducted in a rural area of Kancheepuram district, Tamil Nadu, with a total population of around 16,005.

Materials and Methods:

This study was carried out over a period of 6 months (February-July) using a pre-structured and validated questionnaire. All eligible participants were selected by house-to-house survey and individuals not available on three consecutive visits were excluded from the study. The questionnaire included information on demographic characteristics, lifestyle habits, adherence to HT medication, blood pressure, and body mass index (BMI). Caste was classified based on Tamil Nadu Public Service commission.

Statistical Analysis:

Data were entered in MS Excel and analyzed in SPSS version 16. P value <0.05 was considered statistically significant. Ethical Consideration: Informed verbal consent was obtained prior to data collection. The patient''s adherence to HT medication was assessed using the Morisky 4-Item Self-Report Measure of Medication-taking Behavior [MMAS-4].

Results:

We studied 473 hypertensive patients of which 226 were males and 247 were females. The prevalence of adherence was 24.1% (n = 114) in the study population. Respondents with regular physical activity, non-smokers and non-alcoholics were more adherent to HT medication as compared with respondents with sedentary lifestyle, smoking and alcohol intake (P < 0.005). Based on health belief model, the respondents who perceived high susceptibility, severity, benefit had better adherence compared with moderate and low susceptibility, severity, benefit.     

Feasibility and indicative results from a 12-month low-energy liquid diet treatment and maintenance programme for severe obesity

Background

There is no established primary care solution for the rapidly increasing numbers of severely obese people with body mass index (BMI) > 40 kg/m².

Aim

This programme aimed to generate weight losses of ≥15 kg at 12 months, within routine primary care.

Design and setting

Feasibility study in primary care.

Method

Patients with a BMI ≥40 kg/m² commenced a micronutrient-replete 810–833 kcal/day low-energy liquid diet (LELD), delivered in primary care, for a planned 12 weeks or 20 kg weight loss (whichever was the sooner), with structured food reintroduction and then weight-loss maintenance, with optional orlistat to 12 months.

Result

Of 91 patients (74 females) entering the programme (baseline: weight 131 kg, BMI 48 kg/m², age 46 years), 58/91(64%) completed the LELD stage, with a mean duration of 14.4 weeks (standard deviation [SD] = 6.0 weeks), and a mean weight loss of 16.9 kg (SD = 6.0 kg). Four patients commenced weight-loss maintenance omitting the food-reintroduction stage. Of the remaining 54, 37(68%) started and completed food reintroduction over a mean duration of 9.3 weeks (SD = 5.7 weeks), with a further mean weight loss of 2.1 kg (SD = 3.7 kg), before starting a long-term low-fat-diet weight-loss maintenance plan. A total of 44/91 (48%) received orlistat at some stage. At 12 months, weight was recorded for 68/91 (75%) patients, with a mean loss of 12.4 kg (SD = 11.4 kg). Of these, 30 (33% of all 91 patients starting the programme) had a documented maintained weight loss of ≥15 kg at 12 months, six (7%) had a 10–15 kg loss, and 11 (12%) had a 5–10 kg loss. The indicative cost of providing this entire programme for wider implementation would be £861 per patient entered, or £2611 per documented 15 kg loss achieved.

Conclusion

A care package within routine primary care for severe obesity, including LELD, food reintroduction, and weight-loss maintenance, was well accepted and achieved a 12-month-maintained weight loss of ≥15 kg for one-third of all patients entering the programme.