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Supplementary Tables S1 and S2. Supplementary Table 1. Univariate Cox proportional hazard model analysis using baseline and change in levels of biomarkers with PFS Supplementary Table 2. Multivariate Cox proportional hazard model analysis using baseline and change in levels of biomarkers with PFS

Purpose: This “3+3” phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.Experimental Design: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort.Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1–3.2 mg; 33 with twice-daily dosing of 3.2–12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC0–24 and Cmax increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively).Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients. Clin Cancer Res; 21(21); 4801–10. ©2015 AACR.

Compilation of supplemental tables and figures

Purpose:As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy.Patients and Methods:In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400–640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1–2, while the latter was administered on day 8 of cycles 1–4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression.Results:Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus–negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia.Conclusions:No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.

Background. Preclinical studies have shown that the combined inhibition of EGFR and NF-kB pathways to target the RalB/TBK1 pathway led to synergistic antitumor activity. Based on this rationale, we conducted a Phase I dose-escalation study combining the EGFR inhibitor erlotinib with the NF-kB inhibitor ixazomib in advanced solid tumors. Patients and methods. Patients with advanced solid tumors were eligible. The bayesian optimal interval phase I dose escalation design was used to establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Results. Nineteen patients with a range of solid tumors were enrolled. The most common treatment-related adverse events of any grade were diarrhea (42.1%, 8/19), followed by rash (36.8%, 7/19) and nausea (21.1%, 4/19). The combination RP2D for oral ixazomib was 4.0 mg on days 1, 8, and 15 of a 28-day cycle, with oral erlotinib 150 mg daily. While no patient achieved RECIST v1.1 objective responses, 3 patients with advanced sarcoma experienced durable RECIST v1.1 stable disease ≥ 6 months (8.4, 10.6, and 15.7 months) and the best response was -13% decrease in clear cell sarcoma. Conclusions. The combination of erlotinib and ixazomib was safe and well tolerated among patients with advanced cancer, with preliminary signals of antitumor activity in patients with advanced sarcoma.

Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy. Patients and Methods: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400–640 mg/m2) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1–2, while the latter was administered on day 8 of cycles 1–4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression. Results: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (n = 11), pancreatic cancer (n = 7), immunotherapy-resistant melanoma (n = 2), and human papillomavirus–negative head and neck cancer (n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia. Conclusions: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.

Changes in ambient temperature have been reported as an important risk factor for respiratory diseases among pre-school children. However, there have been few studies so far on the effects of temperature on children respiratory health in developing countries including Vietnam. This study examined the impact of short-term changes in ambient temperature on hospital admissions for acute lower respiratory infection (ALRI) among children aged less than 5 years old in Ho Chi Minh City (HCMC), Vietnam. Data on daily hospital admissions from 2013 to 2017 were collected from two large paediatric hospitals of the city. Daily meteorological data of the same period were also collected. Time series analysis was performed to evaluate the association between risk of hospitalisations and temperatures categorised by seasons, age, and causes. We found that a 1 °C increase in maximum temperature was associated with 4.2 and 3.4% increase in hospital admission for ALRI among children 3–5 years old during the dry season and the rainy season, respectively. Surprisingly, in the rainy season, a rise of 1°C diurnal temperature range (DTR) was significantly associated with a decrease from 2.0 to 2.5% risk of hospitalisation for ALRI among children

Les métastases cérébrales constituent la majorité des tumeurs cérébrales associées le plus souvent à un mauvais pronostic, surtout dans un contexte où la prise en charge des cancers n’est pas toujours optimale. Cette étude a pour objet d’étudier les aspects épidémiologiques, cliniques, thérapeutiques et évolutifs des métastases cérébrales dans deux structures de prise en charge des cancers au Mali. Il s’agissait d’une étude rétrospective allant du 1er janvier 2016 au 31 décembre 2020 dans les services d’oncologie du centre hospitalier Mère - Enfant le Luxemburg et de radiothérapie de l’Hôpital du Mali. Elle a porté sur 92 cas de métastases cérébrales avec un âge moyen de 48 ± 13 ans. Les cancers primitifs les plus pourvoyeurs de métastases cérébrales étaient le cancer du sein suivi de celui du poumon avec respectivement 43% et 28% des cas. Dans notre contexte, les métastases cérébrales ont reçu des traitements médicamenteux et 26% des malades ont reçu une radiothérapie encéphalique totale. Le pronostic des métastases cérébrales était défavorable avec une survie médiane de 2 mois. Brain metastases make up the majority of brain tumors. they are most often associated with a poor prognosis, especially in a context where cancer management is not always optimal. The aim of this work is to study the epidemiological, clinical, therapeutic and outcome aspects of brain metastases in two cancer care structures in Mali. This was a retrospective study from January 1, 2016 to December 31, 2020 in the departments of oncology of the Mother - Child hospital and radiotherapy of the Hôpital du Mali. It focused on 92 cases of brain metastases with a mean age of 48 ± 13 years. The primary cancers most likely to cause brain metastases were breast cancer followed by lung cancer with 43% and 28% of cases, respectively. In our context, brain metastases received drug treatment and 26% of patients received total brain radiotherapy. The prognosis for brain metastases was poor with a median survival of 2 months.

Several systematic reviews have been conducted so far to examine the effect of air pollution on respiratory diseases, but there has not been a corresponding meta-analysis to estimate the effect sizes for wheeze-associated diseases/disorders, which is one of the leading causes of emergency department visits and hospitalizations for children worldwide. The aim of this review is to systematically evaluate the relationship between air pollution and risk of wheeze-associated disorders in children in Southeast Asia. We searched the relevant computerized databases (PubMed, EMBASE, Web of Science, Scopus and Cochrane library) for indexed publications up to July 2018. Finally, eight studies were qualified for performing a random-effect meta-analysis to compute the pooled effect sizes. The results show that each increase of 10 μg/m3 in concentrations of PM2.5, PM1 was associated with 1–2% increase in risk of wheeze-associated disorders. Positive associations were found for PM10, SO2, NO2, NOx but no association was found for CO and O3. We confirmed the strong effect of fine particulate matters on respiratory health and recommend an updated meta-analysis should be done when more studies are available.

This study examined the effect of short-term changes in ambient temperature on hospital admissions among children aged less than 5 years old in Hanoi, Vietnam. Data on daily hospital admissions from January 2010 to June 2014 were collected from two hospitals. Daily meteorological data were obtained for the same period. We applied time series analysis to evaluate the risk of hospitalisation related to hot and cold weather by age and causes. We found that a 1 °C decrease in minimum temperature during the cold weather months was associated with 2.2% increase in hospital admission for respiratory infection among children 3–5 years old. A 1 °C increase in diurnal temperature range (DTR) in cold weather was associated with an increase of 1.9% and 1.7% in hospitalisation for all causes and respiratory infection, respectively, among children

This study aims to provide improved knowledge and evidence on current (1986&ndash, 2015) climate variation based on six rainfall indices over five West African countries (Senegal, Niger, Burkina Faso, Ivory Coast, and Benin) using the Climate Hazards Group InfraRed Precipitation with Station (CHIRPS) dataset. On average, precipitation has increased over the central Sahel and the western Sahel. This increase is associated with increase in the number of rainy days, longer wet spells and shorter dry spells. Over the Guinea Coast, the slight increase in precipitation is associated with an increase in the intensity of rainfall with a shorter duration of wet spells. However, these mean changes in precipitation are not all statistically significant and uniform within a country. While previous studies are focused on regional and sub-regional scales, this study contributes to deliver a climate information at a country level that is more relevant for decision making and for policy makers, and to document climate-related risks within a country to feed impact studies in key sectors of the development, such as agriculture and water resources.

Molecular processes of neuronal learning have been well-described. However, learning mechanisms of non-neuronal cells have not been fully understood at the molecular level. Here, we discuss molecular mechanisms of cellular learning, including conformational memory of intrinsically disordered proteins and prions, signaling cascades, protein translocation, RNAs (microRNA and lncRNA), and chromatin memory. We hypothesize that these processes constitute the learning of signaling networks and correspond to a generalized Hebbian learning process of single, non-neuronal cells, and discuss how cellular learning may open novel directions in drug design and inspire new artificial intelligence methods., cover story of the 2020 April issue of Trends in Biochemical Sciences