This study explored the training needs of substance use disorder (SUD) treatment practitioners in relation to their readiness in treating queer clients. We conducted a series of semi-structured ...interviews (N = 7) based in the Western Cape of South Africa. A thematic analysis identified themes related to treatment structures developed for a binary perception of gender, the burden of discrimination borne by queer clients that may impede treatment, and practitioner interest in further training and development. Our findings suggest that SUD treatment practitioners do not feel fully prepared to treat queer clients and are aware of a need for gender-sensitive training in this area. Improvements to practitioner training and readiness could yield benefits for both clients and practitioners within the treatment space.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
We present a novel way of using one's eye to capture an image of what it "sees" through the use of steady-state visually-evoked potentials (SSVEP). Existing methods leveraging response patterns for ...SSVEP visual image reconstruction show lossy reconstruction and have a lengthy scanning process. With our signal acquisition procedure, data collection requirements are significantly decreased while still improving the signal clarity. The data for image reconstruction were collected from the Oz positioned electrode using a low-cost, wearable electroencephalography (EEG) device. For image reconstruction, software-defined lock-in amplifier (LIA) and discrete Fourier transform (DFT) signal processing methods are analyzed and compared.
We present an investigation into the relationship between steady-state visually-evoked potentials (SSVEPs) and the magnitude, distance, shape, and spatial location of the flashing stimulus relative ...to the participant. We use a wearable electroen-cephalography (EEG) device with the addition of an external occipital electrode for the experiments. SSVEP responses are extracted using the lock-in amplifier and fast Fourier transform algorithms. We then map the responses to what the human eye sees. Our experiments pinpoint the optimal range of stimulus parameters required for stable SSVEP response, identify failure states for flashing stimulus, as well as create a visual map, a vidmap, of the participant's ability to see. The results show that locating the stimulus at the participant's central vision elicits stronger SSVEP response compared to the peripheral vision.
This multicenter, phase II study (NCT03872791) aims to evaluate the efficacy and safety of the anti-PD-L1/CTLA-4 bispecific antibody KN046 combined with nab-paclitaxel in the first-line treatment of ...patients with metastatic triple-negative breast cancer (TNBC). The primary endpoints included objective response rate (ORR) and duration of response (DoR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) rate, safety, and the correlation of PD-L1 status with clinical efficacy. This trial met pre-specified endpoints. 27 female patients were enrolled sequentially to receive KN046 in two dose levels (3 mg/kg or 5 mg/kg). Among the 25 evaluable patients, the ORR achieved 44.0% (95% CI, 24.4% - 65.1%), and the median DoR was not mature. The median PFS reached 7.33 months (95%CI, 3.68 - 11.07 months), and the median OS was 30.92 months (95%CI, 14.75 - NE months). In PD-L1 positive patients, PFS was 8.61 months (versus 4.73 months) and the 2-year OS rate was 62.5% (versus 57.1%) compared to PD-L1 negative patients. Patients tolerated well the combination therapy. In general, KN046 combined with nab-paclitaxel showed favorable efficacy and survival benefits with tolerable toxicity in the first-line treatment of metastatic TNBC, especially PD-L1 positive, which is worth further investigation.
Non-destructive fluorophore diffusion across cell membranes to provide an unbiased fluorescence intensity readout is critical for quantitative imaging applications in live cells and tissues. ...Commercially available small-molecule fluorophores have been engineered for biological compatibility, imparting high water solubility by modifying rhodamine and cyanine dye scaffolds with multiple sulfonate groups. The resulting net negative charge, however, often renders these fluorophores cell-membrane-impermeant. Here we report the design and development of our biologically compatible, water-soluble and cell-membrane-permeable fluorophores, termed OregonFluor (ORFluor). By adapting previously established ratiometric imaging methodology using bio-affinity agents, it is now possible to use small-molecule ORFluor-labelled therapeutic inhibitors to quantitatively visualize their intracellular distribution and protein target-specific binding, providing a chemical toolkit for quantifying drug target availability in live cells and tissues.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Single-molecule tracking (SMT) offers rich information on the dynamics of underlying biological processes, but multicolor SMT has been challenging due to spectral cross talk and a need for multiple ...laser excitations. Here, we describe a single-molecule spectral imaging approach for live-cell tracking of multiple fluorescent species at once using a single-laser excitation. Fluorescence signals from all the molecules in the field of view are collected using a single objective and split between positional and spectral channels. Images of the same molecule in the two channels are then combined to determine both the location and the identity of the molecule. The single-objective configuration of our approach allows for flexible sample geometry and the use of a live-cell incubation chamber required for live-cell SMT. Despite a lower photon yield, we achieve excellent spatial (20–40 nm) and spectral (10–15 nm) resolutions comparable to those obtained with dual-objective, spectrally resolved Stochastic Optical Reconstruction Microscopy. Furthermore, motions of the fluorescent molecules did not cause loss of spectral resolution owing to the dual-channel spectral calibration. We demonstrate SMT in three (and potentially more) colors using spectrally proximal fluorophores and single-laser excitation, and show that trajectories of each species can be reliably extracted with minimal cross talk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Endothelial dysfunction plays a critical role in the development of type 2 diabetes (T2DM). T-cadherin (T-cad) has gained recognition as a regulator of endothelial cell (EC) function. The present ...study examined whether T-cad deficiency increases vascular vulnerability in T2DM.
Vascular segments were isolated from WT or T-cad knockout mice. Endothelial function, total NO accumulation, and the expression of T-cad related proteins were determined.
Ach and acidified NaNO2 induced similar vasorelaxation in WT groups. T-cad KO mice exhibited normal response to acidified NaNO2, but manifested markedly reduced response to Ach. NO accumulation was also decreased in T-cad KO group. T-cad expression was reduced in WT mice fed 8 weeks of high fat diet (HFD). Furthermore, exacerbated reduction of vasorelaxation was observed in T-cad KO mice fed 8 weeks of HFD.
In the current study, we provide the first in vivo evidence that T-cadherin deficiency causes endothelial dysfunction in T2DM vascular segments, suggesting the involvement of T-cad deficiency in T2DM pathogenesis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: Despite recent FDA approval of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of mTNBC, the overall survival benefit of these patients ...remains modest. We conducted a phase 2 study to assess the efficacy and safety of anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in mTNBC patients (pts) regardless of PD-L1 status. Preliminary results have been delivered in 2021 AACR1, here we reported the final results of the progression-free survival (PFS) and overall survival (OS) analysis. Methods: This study enrolled pts with treatment-naïve locally advanced inoperable or metastatic TNBC. Eligible pts received nab-paclitaxel plus KN046 at two dose levels (DL1: KN046 3 mg/kg Q2W or DL2: KN046 5 mg/kg Q2W). Tumor response was evaluated Q8W per RECIST 1.1. The primary endpoint included objective response (ORR) and duration of response (DoR), secondary included disease control rate (DCR), clinical benefit rate (CBR), PFS, 1-year/2-year OS rate and safety/tolerability. Results: As of May 9, 2022 (cut-off date), 27 pts were enrolled into DL1 (n=16) and DL2 (n=11). Median patient age in the study was 50 years (range, 33-70 years). At baseline, 52% and 48% of patients had ECOG PS of 0 and 1, respectively. By the cut-off date, there are 1 pts under treatment and 16pts alive. The median study follow-up time was 26.3 months (95% CI, 20.7 - 29.8). Based on the intent-to-treatment (ITT) population, the confirmed ORR was 33.3% (95% CI, 16.5% - 54.0%), DCR was 88.9% (95% CI, 70.8% - 97.7%), and CBR was 48.1% (95% CI, 28.7% - 68.1%), which remained stable compared with last reported in 2021 1. The DoR was 11.9 (95% CI, 5.6 - NR) months. The median PFS was 7.3 (95% CI, 3.7 - 13.7) months. The median OS is immature, the preliminary result is 27.7 (95% CI, 14.8 - NR) months, and the 2-year OS rate was 60.1% (95%CI, 37.2% - 76.9%). Among the 11 pts with PD-L1 positive (≥1% IC), confirmed ORR was 45.5% (95%CI, 16.7% - 76.6%) and mPFS was 8.61 (95%CI, 1.6 - 13.8) months. Both PD-L1 positive and negative pts derived OS benefit from the combination treatment, with the 2-year OS rate of 57.14% (95%CI, 25.4% - 79.6%) and 62.5% (95%CI, 22.9% - 86.1%) respectively. Patients tolerated well to combination therapy in this trial. The most common reported treatment related adverse event (TRAEs) were ALT elevation (13 pts, 48%), AST elevation (12 pts, 44%), pyrexia (9 pts, 33%), neutropenia (8 pts, 30%), and anemia (7 pts, 26%). Grade ≥3 TRAEs (≥10%) were neutropenia (7 pts, 26%), leukopenia (6 pts, 22%) and AST elevation (5 pts, 15%). 13 pts (48%) experienced immune related adverse events (irAEs), and only 3 irAEs (11%) were grade 3. The incidence of SAE was 33%, with no TRAE leading to death. Conclusions: The combination therapy of KN046 plus nab-paclitaxel has shown favorable clinical efficacy in mTNBC, especially in PD-L1 positive patients. By the cut-off date, the mOS is not mature and there is still more than half of pts alive, which demonstrated an encouraging 2-year OS rate. Pts in this trial tolerated well to the combination therapy and safety profile was manageable. Clinical trial information: NCT03872791 Reference 1. Cancer Res (2021) 81 (13_Supplement): 1660.
Citation Format: Qiao Li, Qingyuan Zhang, Yue Zhang, Quchang Ouyang, Qiang Liu, Tao Sun, Feng Ye, Baochun Zhang, Ting Xu, Summer Xia, Karl Zhang, Bangyong Zhang, Binghe Xu. PD11-10 Efficacy, Safety, and Tolerability of KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in combination with Nab-paclitaxel in Metastatic Triple-negative Breast Cancer (mTNBC):Final results of the Phase II trial abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-10.
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