Realization of a high power optical trapping setup free from thermal lensing effects

Transmission of high power laser beams through partially absorbing materials modifies the light propagation via a thermally-induced effect known as thermal lensing. This may cause changes in the beam waist position and degrade the beam quality. Here we characterize the effect of thermal lensing associated with the different elements typically employed in an optical trapping setup for cold atoms experiments. We find that the only relevant thermal lens is represented by the $TeO_2$ crystal of the acousto-optic modulator exploited to adjust the laser power on the atomic sample. We then devise a simple and totally passive scheme that enables to realize an inexpensive optical trapping apparatus essentially free from thermal lensing effects

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma

BET inhibitors; Glioblastoma; PharmacokineticsInhibidores de BET; Glioblastoma; FarmacocinéticaInhibidors de BET; Glioblastoma; FarmacocinèticaBackground Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.This study was sponsored by Celgene, a Bristol Myers Squibb company

Realization of a Cold Mixture of Fermionic Chromium and Lithium Atoms

We report on the production of a novel cold mixture of fermionic $^{53}$Cr and $^{6}$Li atoms delivered by two Zeeman-slowed atomic beams and collected within a magneto-optical trap (MOT). For lithium, we obtain clouds of up to $4 \,10^8$ atoms at temperatures of about $500\,\mu$K. A gray optical molasses stage allows us to decrease the gas temperature down to $45(5)\,\mu$K. For chromium, we obtain MOTs comprising up to $1.5\, 10^6$ atoms. The availability of magnetically trappable metastable $D$-states, from which $P$-state atoms can radiatively decay onto, enables to accumulate into the MOT quadrupole samples of up to $10^7$ $^{53}$Cr atoms. After repumping $D$-state atoms back into the cooling cycle, a final cooling stage decreases the chromium temperature down to $145(5)\,\mu$K. While the presence of a lithium MOT decreases the lifetime of magnetically trapped $^{53}$Cr atoms, we obtain, within a 5 seconds duty cycle, samples of about $4\, 10^6$ chromium and $1.5\,10^8$ lithium atoms. Our work provides a crucial step towards the production of degenerate Cr-Li Fermi mixtures.Comment: 14 pages, 8 figure

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Atezolizumab; Isatuximab; Solid tumorsAtezolizumab; Isatuximab; Tumores sólidosAtezolizumab; Isatuximab; Tumors sòlidsBackground The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon’s two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.This work was sponsored by Sanofi (no grant number)

First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer

Càncer avançat; Factor de creixement transformador betaAdvanced Cancer; Transforming Growth Factor betaCáncer avanzado; Factor de crecimiento transformador betaPurpose: A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. Patients and Methods: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). Results: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. Conclusions: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted

Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFβ) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors

Pharmacodynamic; Transforming growth factor-beta; Advanced solid tumorsFarmacodinámica; Factor de crecimiento transformante beta; Tumores sólidos avanzadosFarmacodinàmica; Factor de creixement transformador beta; Tumors sòlids avançatsSAR439459, a ‘second-generation’ human anti-transforming growth factor-beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune-excluded’ to ‘immune-infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.This study was sponsored by Sanofi

Van der Waals explosion of cold Rydberg clusters

We report on the direct measurement in real space of the effect of the van der Waals forces between individual Rydberg atoms on their external degrees of freedom. Clusters of Rydberg atoms with interparticle distances of around 5μm are created by first generating a small number of seed excitations in a magneto-optical trap, followed by off-resonant excitation that leads to a chain of facilitated excitation events. After a variable expansion time the Rydberg atoms are field ionized, and from the arrival time distributions the size of the Rydberg cluster after expansion is calculated. Our experimental results agree well with a numerical simulation of the van der Waals explosion

Phase Ib/II study of ceritinib in combination with ribociclib in patients with ALK-rearranged non–small cell lung cancer

ALK inhibitors; Ceritinib; RibociclibInhibidores de ALK; Ceritinib; RibociclibInhibidors d'ALK; Ceritinib; RibociclibBackground Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non–small cell lung cancer (NSCLC). Methods This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy. Results Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300–450 mg/day) and ribociclib (range, 100–300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4–57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5–25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5–25.1). Safety profile of the combination therapy was consistent with single-agent safety data. Conclusion Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.This study was supported by Novartis Pharmaceuticals Corporation

Psychometric Testing of the Mutuality Scale in Patients and Caregiver Dyads After the Onset of Coronary Heart Disease

This study investigates the psychometric properties of the Mutuality Scale in a sample of patient-caregiver dyads following a recent episode of coronary heart disease. A cross-sectional analysis was conducted. Factorial validity was tested with confirmatory factory analysis. Internal consistency reliability was investigated with the model-based internal consistency reliability index. Pearson's correlation coefficient was used to test convergent validity between mutuality and other theoretical and empirical variables associated with it. We included 150 patient-caregiver dyads (patient: mean age 65 years, 77% males, 71% married; caregiver: mean age 54 years, 21% males, 71% married). The CFA testing the theoretical four-factors (love, shared pleasurable activities, shared values, and reciprocity) of mutuality demonstrated adequate fit to the data in both the patient and caregiver version of the scale. Reliability estimates were adequate for the whole scale (model-based internal consistency index = 0.95). Significant positive correlations were observed between mutuality and self-care behaviors, and caregiver preparedness, supporting convergent validity. The Mutuality Scale demonstrated satisfactory structural and convergent validity and reliability in patient-caregiver dyads after the onset of a coronary heart disease event