Antibody–drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold ...significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors. In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response‐guided dosing recommendations; and randomized dose‐finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next‐generation ADCs.
STIM1 (stromal interaction molecule 1), an endoplasmic reticulum Ca(2+) sensor that triggers the store-operated Ca(2+) entry activation, has recently been implicated in cancer progression. However, ...the role of STIM1 in the progression and metastasis of colorectal cancer (CRC) has not been addressed. In this study, we confirmed increased expression of STIM1 in highly invasive CRC cell lines. Enhanced expression of STIM1 promoted CRC cell metastasis in vitro and in vivo, whereas silencing of STIM1 with small interfering RNA resulted in reduced metastasis. Ectopic expression of STIM1 in CRC cells induced epithelial-to-mesenchymal transition (EMT), whereas silencing of STIM1 had the opposite effect. Furthermore, STIM1 expression was markedly higher in CRC tissues than in adjacent noncancerous tissues. STIM1 overexpression correlated with poor differentiation and higher tumor node metastasis stage. CRC patients with positive STIM1 expression had poorer prognoses than those with negative STIM1 expression. Moreover, STIM1 was found to be a direct target of miR-185, a microRNA (miRNA) that has not previously been reported to be involved in EMT, in both CRC tissues and cell lines. Taken together, these findings demonstrate for the first time that STIM1 promotes metastasis and is associated with cancer progression and poor prognosis in patients with CRC. In addition, we show that expression of STIM1 is regulated by a posttranscriptional regulatory mechanism mediated by a new EMT-related miRNA. This novel miR-185-STIM1 axis promotes CRC metastasis and may be a candidate biomarker for prognosis and a target for new therapies.
Abstract
V410 Aur is a known deep and low-mass-ratio contact binary with a spectroscopically tertiary component and a visual companion. However, the physical and orbital properties of the tertiary ...are unknown. We constructed (
O
−
C
) curve with 117 new eclipse times and those collected from the literature, which shows a cyclical variation with a period of 25.44 (±1.17) yr and a projected semimajor axis of 0.0348 (±0.0021) days while it undergoes a long-term period decrease at a rate of
dP
/
dt
= −1.58 × 10
−7
daysyr
−1
. The cyclical variation is analyzed for the light-travel time effect. The minimum mass of the third body is determined as 1.39 (±0.13)
M
⊙
that is much larger than the inferred value (0.97
M
⊙
) of spectroscopic investigation, which indicates that the spectroscopically tertiary is a single-lined spectroscopic binary with an unseen component. The maximum orbital semimajor axis 6.19 (±0.67) au of the third body is determined. Gaia detected a visual companion to V410 Aur at practically the same distance from the Sun nicely confirming the physical bond. These results reveal that V410 Aur contains a single-lined spectroscopic binary with a visual companion in a quintuple stellar system. TESS photometric solutions confirmed that V410 Aur is a deep overcontact binary with a fill-out factor of 73.83(88)% where the additional light contribution is about 24.80(18)%. The continuous variations of light curves are explained by the evolution of a dark spot on the more massive component. The parabolic variation in the (
O
−
C
) curve may be caused by the mass transfer from the massive component to the less massive one in the deep overcontact binary.
Abstract
As the plasma boundary between two distinct plasma populations, dipolarization fronts (DFs) host abundant kinetic-scale substructures that change their normal directions and thus cause their ...deformation. However, studies on such deformation caused by an electron vortex have been lacking. Here, we present novel observations of a subion-scale magnetic hump (MHu) associated with an oblique electron vortex at a DF through strengthening three components of the magnetic field. A radial electric field in the MHu, showing bipolar variation, is also associated with the electron vortex as it is mainly ascribed to the electron convection term. There is apparent energy conversion (
J
→
·
E
→
∼−0.3 nw m
−3
) from the particles to the electromagnetic field in the MHu’s leading part, which is accompanied by inflow and outflow of electromagnetic energy (nonzero
∇
·
S
→
). The other regions of the DF host opposite energy conversion (
J
→
·
E
→
> 0). Broadband parallel electrostatic waves are also observed in the MHu. Our study provides insights into the kinetic-scale processes at DFs.
The purposes of this study were to establish thresholds for improvement in patient-reported outcome scores that signify the minimal clinically important difference (MCID), substantial clinical ...benefit (SCB), and patient acceptable symptomatic state (PASS) after biceps tenodesis (BT) and to assess patient variables that are associated with these clinically important outcomes.
A prospectively maintained institutional shoulder registry was queried for patients undergoing isolated BT between 2014 and 2017. Anchor-based and distribution-based approaches were used to calculate the MCID whereas an anchor-based method was used to calculate the SCB and PASS for the Constant-Murley score, Single Assessment Numerical Evaluation (SANE) score, and American Shoulder and Elbow Surgeons score.
A total of 123 patients who underwent isolated BT were included for analysis. The MCID, SCB, and PASS calculated for the American Shoulder and Elbow Surgeons score were 11.0, 16.8, and 59.6, respectively. For the Constant-Murley score, the calculated MCID and PASS were 3.8 and 19.5, respectively. The MCID, SCB, and PASS calculated for the SANE score were 3.5, 5.8, and 65.5, respectively. The following patient variables were significantly associated with decreased odds of achieving the MCID: workers' compensation status, male sex, and higher preoperative SANE score. Patients with a history of ipsilateral shoulder surgery had significantly reduced odds of achieving SCB. The only factor significantly associated with failing to reach the PASS was workers' compensation status.
This study established values for the MCID, SCB, and PASS after BT without concomitant rotator cuff repair. Workers' compensation status, previous shoulder surgery, male sex, and higher preoperative patient-reported outcome measure scores are associated with lower odds of achieving clinically significant improvement after BT.
Agnathan fish hold a key position in vertebrate evolution, especially regarding the origin of the head and neural-crest-derived tissue. In contrast to amphioxus, lampreys and other vertebrates ...possess a complex brain and placodes that contribute to well-developed eyes, as well as auditory and olfactory systems. These sensory sytems were arguably a trigger to subsequent vertebrate diversifications. However, although they are known from skeletal impressions in younger Palaeozoic agnathans, information about the earliest records of these systems has been largely wanting. Here we report numerous specimens of the Lower Cambrian vertebrate Haikouichthys ercaicunensis, until now only known from the holotype. Haikouichthys shows significant differences from other fossil agnathans: key features include a small lobate extension to the head, with eyes and possible nasal sacs, as well as what may be otic capsules. A notochord with separate vertebral elements is also identifiable. Phylogenetic analysis indicates that this fish lies within the stem-group craniates. Although Haikouichthys somewhat resembles the ammocoete larva of modern lampreys, this is because of shared general craniate characters; adult lampreys and hagfishes (the cyclostomes if monophyletic) are probably derived in many respects.
Background:
Although patellofemoral instability is among the most prevalent knee disorders, the management of patients with this condition is complex and remains variable, given the lack of ...long-term, high-level clinical outcome studies to compare various operative and nonoperative modalities.
Purpose:
To discover a consensus within treatment controversies in patellofemoral instability among experienced knee surgeons with a specific interest in the patellofemoral joint.
Study Design:
Expert opinion; Level of evidence, 5.
Methods:
A 3-step modified Delphi technique was used to establish a consensus. A 34-question, case-based online survey regarding patellofemoral instability was distributed to all active members of the International Patellofemoral Study Group. Consensus statements were generated if at least 66% of the respondents agreed and then redistributed to the same panel. Modifications to the consensus statements were made based on the iterative feedback process until no discordance was encountered in the third stage.
Results:
Eight consensus statements were achieved. Nonoperative management is the current standard of care for a first-time dislocation in the absence of an osteochondral fragment or loose body requiring excision (100% agreement). In patients with a first-time dislocation with an operative osteochondral fracture requiring excision or repair, patellar instability should be addressed concurrently (89% agreement). Recurrent instability should be treated surgically, with most surgeons favoring medial reconstruction (77%-86% agreement). While there is general agreement that bony procedures should be performed to correct underlying bony deformities, there is no consensus regarding the most appropriate type of procedure performed. Lateral release should not be performed in isolation for the treatment of patellar instability (89% agreement).
Conclusion:
Despite the consensus generated in this study, our current understanding remains limited by a lack of high-level evidence as well as the numerous complex variables influencing treatment decision making. High-quality, multicenter randomized controlled trials, particularly those directly comparing specific surgical treatment methods while controlling for underlying risk factors, are needed to address these areas of uncertainty.
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between ...patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients' blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.
•SPIONs’ neurotoxicity in PC12 cells, mouse hippocampus and striatum was detected.•SPIONs had a dose-dependent cytotoxic in PC12 cells at 60–200 ug/mL.•SPIONs decreased TH+ fiber density, motor ...coordination and spatial memory of mice.•SPIONs-induced neurotoxicity might be mediated through the JNK signaling pathway.
Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used as theranostic drug-carrier and MRI contrast agent. Their potential effects are still in blank while SPIONs are used for brain. The present study aims to investigate SPIONs’ neurotoxicity in vitro and in vivo using stereotaxic technique. By co-incubating SPIONs with dopaminergic neuronal PC12 cells, we found that SPIONs had a dose-dependent cytotoxic in PC12 cells at 60–200 ug/mL but not at 10–50 ug/mL, it reduced cell viability, decreased the capacity of PC12 cells to extend neurites in response to nerve growth factor (NGF), induced a reduction of the tyrosine hydroxylase protein, while increasing PC12 cell apoptosis. Accordingly, the no-observed-adverse-effect level (NOAEL) of current SPIONs was 50 ug/mL in vitro, which would be useful for human health risk assessment. While directly injecting the SPIONs into the dorsal striatum or hippocampus, 7 and 14 days after surgery, nanoparticles decreased the TH+ fiber density in both the dorsal striatum and the hippocampus. A behavioral evaluation demonstrated that SPIONs attenuated the animals’ motor coordination and spatial memory, as evaluated by the rotarod test and the Morris water maze. We further examined mitogen-activated protein kinase (MAPK) activation and found that c-Jun N-terminal kinase (JNK) was activated after SPIONs treatment. It suggests that the SPIONs-induced neurotoxicity might be mediated through the JNK signaling pathway. SPIONs could possibly induce neurotoxic effects on the dorsal striatum and hippocampus.
PDF
