By combining angle-resolved photoemission spectroscopy and quantum oscillation measurements, we performed a comprehensive investigation on the electronic structure of LaSb, which exhibits ...near-quadratic extremely large magnetoresistance (XMR) without any sign of saturation at magnetic fields as high as 40 T. We clearly resolve one spherical and one intersecting-ellipsoidal hole Fermi surfaces (FSs) at the Brillouin zone (BZ) center Γ and one ellipsoidal electron FS at the BZ boundary X. The hole and electron carriers calculated from the enclosed FS volumes are perfectly compensated, and the carrier compensation is unaffected by temperature. We further reveal that LaSb is topologically trivial but shares many similarities with the Weyl semimetal TaAs family in the bulk electronic structure. Based on these results, we have examined the mechanisms that have been proposed so far to explain the near-quadratic XMR in semimetals.
Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a ...combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.
In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg two 300-mg tablets twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.
The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).
In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).
The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition ...of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.
Size effects (SEs) exist in many domains, and are caused by changes in the values of parameters of materials, structures, or systems individually or collectively known as size effect factors. SEs ...induce a variety of scale-dependent behaviours, phenomena, and performances during the multiscale processing and manufacturing of materials, such as the macro-, meso-, and microscale ones examined by the researches described in this paper. Furthermore, the parts and components fabricated from multiscale processing and manufacturing exhibit the scatters of quality and properties. This paper uses multiscale machining and deformation-based manufacturing as the case studies of material processing and manufacturing to review and analyse SEs and their manifestations. The current status of multiscale manufacturing research and its possible future avenues are articulated and discussed, and key problems that must be solved and unknowns that must be understood are highlighted. This paper thus presents a broad understanding and insight into SEs that influence the material processing and manufacturing for making multiscale parts and components. It also examines the bottleneck problems generated by SEs in such processing and manufacturing arena, and how these can be solved to enable the high efficiencies of multi-scale materials processing and manufacturing to be realised.
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•Size effect (SE) factors and their classification are given.•Manifestations of SEs and the classification into three identified phenomena are articulated.•The SE available mechanisms are summarised and the loopholes are analysed.•The SE-induced behaviour and phenomena are delineated.•SE caused scatters are explicated and the impacts in manufacturing are discussed.
Despite the growing interest in the use of ultrasound (US) imaging to guide performance of regional anaesthetic procedures such as peripheral nerve blocks, controversy still exists as to whether US ...is superior to previously developed nerve localization techniques such as the use of a peripheral nerve stimulator (PNS). We sought to clarify this issue by performing a systematic review and meta-analysis of all randomized controlled trials that have compared these two methods of nerve localization.
We searched Ovid MEDLINE®, the Cochrane Central Register of Controlled Trials®, and Google Scholar databases and also the reference lists of relevant publications for eligible studies. A total of 13 studies met our criteria and were included for analysis. Studies were rated for methodological quality by two reviewers. Data from these studies were abstracted and synthesized using a meta-analysis.
Blocks performed using US guidance were more likely to be successful risk ratio (RR) for block failure 0.41, 95% confidence interval (CI) 0.26–0.66, P<0.001, took less time to perform (mean 1 min less to perform with US, 95% CI 0.4–1.7 min, P=0.003), had faster onset (29% shorter onset time, 95% CI 45–12%, P=0.001), and had longer duration (mean difference 25% longer, 95% CI 12–38%, P<0.001) than those performed with PNS guidance. US guidance also decreased the risk of vascular puncture during block performance (RR 0.16, 95% CI 0.05–0.47, P=0.001).
US improves efficacy of peripheral nerve block compared with techniques that utilize PNS for nerve localization. Larger studies are needed to determine whether or not the use of US can decrease the number of complications such as nerve injury or systemic local anaesthetic toxicity.
Circadian rhythms are endogenous oscillations of physiological and behavioral phenomena with period length of ∼24 hr. A mutation in human Period 2 (hPER2), a gene crucial for resetting the central ...clock in response to light, is associated with familial advanced sleep phase syndrome (FASPS), an autosomal dominant condition with early morning awakening and early sleep times. The FASPS hPER2 S662G mutation resulted in PER2 being hypophosphorylated by casein kinase I (CKI) in vitro. We generated transgenic mice carrying the FASPS hPER2 S662G mutation and faithfully recapitulate the human phenotype. We show that phosphorylation at S662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. Altering CKIδ dosage modulates the S662 phenotype demonstrating that CKIδ can regulate period through PER2 in vivo. Modeling a naturally occurring human variant in mice has yielded novel insights into PER2 regulation.
Aim
3‐Phenyllactic acid (3‐PLA) has been widely used in food and material industries. Three Lactobacillus crustorum strains have shown greater 3‐PLA production ability in our previous study. The ...objectives of this study were to further improve 3‐PLA yields in batch and continuous fermentation systems using of free‐whole‐cells of the three L. crustorum strains.
Materials and Results
The fermentation conditions of free‐whole‐cells of the three L. crustorum strains for 3‐PLA production were optimized. Among these strains, L. crustorum NWAFU 1078 showed excellent reusability and significantly (P < 0·05) greater 3‐PLA production ability than the other strains after 10th recycle. The strain possesses three l‐lactate dehydrogenase and three d‐lactate dehydrogenase catalysing 3‐PLA production from phenylpyruvic acid (PPA). Under the optimal conditions, the strain produced 15·2 mmol l−1 3‐PLA (76% PPA conversion rate) in a batch fermentation system and 6·5 mmol l−1 h−1 3‐PLA (55% PPA conversion rate) in a continuous fermentation system using a 0·6 dilution rate.
Conclusions
Free‐whole‐cells of L. crustorum NWAFU 1078 showed excellent reusability and higher 3‐PLA yields under optimal biotransformation conditions in both batch and continuous fermentation systems.
Significance and Impact of the Study
This study provides the possibility to use the free‐whole‐cells of L. crustorum NWAFU 1078 as a biocatalyst for effective production of 3‐PLA.
Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology ...approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.
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