Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

Relationship between coordination variability and Osgood-Schlatter disease in male junior youth soccer players -cross-sectional study using an inertial measurement unit.

BACKGROUND: Osgood-Schlatter disease is a common overuse injury, and motor coordination is discussed as a risk factor; however, no reports have examined motor coordination in young soccer players with Osgood-Schlatter disease. This study aimed to investigate the difference in motor coordination between Osgood-Schlatter disease-affected and non-affected soccer players on a junior youth soccer team. METHODS: This cross-sectional study investigated 35 young soccer players of 12-15 years of age, who completed a self-administered questionnaire covering general information, injury history, and athletic experience. An inertial measurement unit was attached to the participant's thoracic spine, lumbar spine, pelvis, thigh, and lower leg. The sagittal plane tilt angle of each body segment during squatting was analyzed. The continuous relative phase was calculated using the sagittal plane tilt angle. The mean absolute relative phase and continuous relative phase variabilities were calculated and compared between Osgood-Schlatter disease-affected and non-affected players. FINDINGS: The sagittal plane tilt angle of each body segment during static standing and maximum flexion did not differ between the two groups. However, the Osgood-Schlatter disease group had significantly less continuous relative phase variability between the lumbar spine and pelvis (P < 0.01, Cohen's d = 0.91). The Osgood-Schlatter disease group had significantly fewer participants with other sports experience (P = 0.032, φ = 0.36). INTERPRETATION: Dysfunctional lower trunk and hip muscles may be leading to Osgood-Schlatter disease. It is suggested that a variety of physical activities should be performed in the junior age group to allow players to acquire a variety of movement patterns.

Structure-Activity Relationship Studies of SARS-CoV-2 Main Protease Inhibitors Containing 4-Fluorobenzothiazole-2-carbonyl Moieties.

The main protease (Mpro) of SARS-CoV-2 is an attractive target for the development of drugs to treat COVID-19. Here, we report the design, synthesis, and structure-activity relationship (SAR) studies of highly potent SARS-CoV-2 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro inhibitors (3) and (4), several hybrid molecules of these previous compounds combined with nirmatrelvir (1) were designed and synthesized. Compounds such as TKB245 (5) and TKB248 (6), containing a 4-fluorobenzothiazole moiety at the P1' site, are highly effective in the blockade of SARS-CoV-2 replication in VeroE6 cells. Replacement of the P1-P2 amide with the thioamide surrogate in TKB248 (6) improved its PK profile in mice compared to that of TKB245 (5). A new diversity-oriented synthetic route to TKB245 (5) derivatives was also developed. The results of the SAR studies suggest that TKB245 (5) and TKB248 (6) are useful lead compounds for the further development of Mpro inhibitors.

Potent and biostable inhibitors of the main protease of SARS-CoV-2.

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion.

SIGNIFICANCE: This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.

In-process measurement of a keyhole using a low-coherence interferometer with a high repetition rate.

The shape of an instance hole (keyhole) created via a high-power laser was measured using a low-coherence interferometer with the following parameters: repetition rate, 10 MHz; center wavelength, 1550 nm; absolute spatial resolution, 10 µm; and measurement range, 5 mm. The keyhole was created on a 3-mm-thick stainless-steel plate using a high-power laser with 8-kW peak power and 1070-nm center wavelength. The cross-sectional area of the keyhole was measured to be 0.42 mm × 0.78 mm (width × depth) using the interferometer, and its side dimension was 0.46 mm × 0.78 mm (width × depth).

Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models.

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

Intersubject and Intrasubject Variability of Potential Plasma and Urine Metabolite and Protein Biomarkers in Healthy Human Volunteers.

A limited understanding of intersubject and intrasubject variability hampers effective biomarker translation from in vitro/in vivo studies to clinical trials and clinical decision support. Specifically, variability of biomolecule concentration can play an important role in interpretation, power analysis, and sampling time designation. In the present study, a wide range of 749 plasma metabolites, 62 urine biogenic amines, and 1,263 plasma proteins were analyzed in 10 healthy male volunteers measured repeatedly during 12 hours under tightly controlled conditions. Three variability components in relative concentration data are determined using linear mixed models: between (intersubject), time (intrasubject), and noise (intrasubject). Biomolecules such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, platelet-derived growth factor C, and cathepsin D with low noise potentially detect changing conditions within a person. If also the between component is low, biomolecules can easier differentiate conditions between persons, for example cathepsin D, CD27 antigen, and prolylglycine. Variability over time does not necessarily inhibit translatability, but requires choosing sampling times carefully.

Identification and Characterization of a New Carboxylesterase 2 Isozyme, mfCES2C, in the Small Intestine of Cynomolgus Monkeys.

In contrast to a single human carboxylesterase 2 (CES2) isozyme (hCE2), three CES2 genes have been identified in cynomolgus monkeys: mfCES2A, mfCES2B, and mfCES2C . Although mfCES2A protein is expressed in several organs, mfCES2B is a pseudogene and the phenotype of the mfCES2C gene has not yet been clarified in tissues. In previous studies, we detected an unidentified esterase in the region of CES2 mobility upon nondenaturing PAGE analysis of monkey intestinal microsomes, which showed immunoreactivity for anti-mfCES2A antibody. The aim of the present study was to identify this unidentified esterase from monkey small intestine. The esterase was separated on nondenaturing PAGE gel and digested in-gel with trypsin. The amino acid sequences of fragmented peptides were analyzed by tandem mass spectrometry. The unidentified esterase was shown to be identical to mfCES2C (XP_015298642.1, predicted from the genome sequence data). mfCES2C consists of 559 amino acid residues and shows approximately 90% homology with mfCES2A (561 amino acid residues). In contrast to the ubiquitous expression of mfCES2A, mfCES2C is only expressed in the small intestine, kidney, and skin. The hydrolytic properties of recombinant mfCES2C, expressed in HEK293 cells, with respect to p-nitrophenyl derivatives, 4-methylumbelliferyl acetate, and irinotecan were similar to those of recombinant mfCES2A. However, mfCES2C showed a hydrolase activity for O-n-valeryl propranolol higher than mfCES2A. It is concluded that the previously unidentified monkey intestinal CES2 is mfCES2C, which shows different hydrolytic properties to mfCES2A, depending on the substrate. SIGNIFICANCE STATEMENT: In the present research, we determined that mfCES2C, a novel monkey CES2 isozyme, is expressed in the small intestine and kidney of the cynomolgus monkey. Interestingly, mfCES2C showed a relatively wide substrate specificity for ester-containing compounds. These findings may, in early stages of drug development, support the use of in vitro-to-in vivo extrapolation for the intestinal hydrolysis of ester drugs in the cynomolgus monkey.

Master-slave carrier recovery for M-QAM multicore fiber transmission.

Master-slave carrier recovery is a digital signal processing technique that uses correlated phase noise in multi-channel receivers to eliminate redundant carrier recovery blocks. In this paper we experimentally investigate the performance of master-slave carrier recovery for multicore fiber transmission in the presence of inter-channel nonlinear interference. Using a triple parallel loop setup we jointly receive three spatial channels in a 7-core fiber for transmission distances of up to 1600 km. We find that an increased launch power causes a moderate penalty on the slave channels. Furthermore, we study the penalty from a non-zero inter-core skew.

Demonstration of PAM4-OCDM system with electrical amplitude-level pre-tuning and post-equalization for data centers applications.

A PAM4-OCDM system with optical multi-/demultiplexing and electrical pre-/post-processing is proposed for short-reach applications. We experimentally demonstrate, for the first time, a power-efficient 4 OC x 10 GSymbol/s PAM4-OCDM system. The four PSK-OCs are simultaneously generated using a single light source and a passive multiport optical encoder and received by a single optical decoder and cascaded DSP. The effectiveness of the electrical-domain amplitude level pre-tuning and post-equalizer are demonstrated, considering different values of shot and beat noises.

Ecotypic divergences of the alpine herb Potentilla matsumurae adapted to fellfield-snowbed habitats across a series of mountain sky islands.

PREMISE: Divergent selection due to environmental heterogeneity can lead to local adaptation. However, the ecological and evolutionary processes of local adaptation that occurs across multiple regions are often unknown. Our previous studies reported on the ecotypic divergence within a local area of variation of Potentilla matsumurae, an alpine herb adapted to the fellfield-snowbed environment. Here we investigated large-scale geographic patterns of ecotypic differentiation in this species to infer local adaptation and selective forces across multiple regions. METHODS: We compiled information on the overall distributions of fellfield and snowbed habitats on the mountains in Japan across the distribution of the species. Next, we conducted common garden experiments to test the adaptive divergence of the fellfield-snowbed plants derived from multiple regions. Finally, we evaluated phylogeographic structures based on cpDNA and allozyme variations and inferred the evolutionary history of ecotype differentiation. RESULTS: The mosaic distribution of the fellfield-snowbed ecotypes across isolated mountaintops constitutes indirect evidence for habitat-specific natural selection. The significant difference in survivorship between the ecotypes observed in a controlled snow environment provides more substantial evidence of local selection. Phylogeographic structures support the hypothesis that ecotypic divergence events from fellfield to snowbed populations occurred independently in at least two distinct regions. CONCLUSIONS: Ecotypic divergence of P. matsumurae has occurred across a series of mountain sky islands. Local selection in snowy environments is a driving force that maintains the divergent ecotypes across multiple mountain regions and can contribute to the diversification of plants in heavy-snow regions.

Long distance crosstalk-supported transmission using homogeneous multicore fibers and SDM-MIMO demultiplexing.

We propose and evaluate the use of spatial-division multiplexing (SDM) multiple input multiple output (MIMO) systems to support long distance transmission using single-mode homogeneous multicore fibers. We show that on a uniform link with per-span inter-core skew compensation, the required SDM-MIMO memory length corresponds to the largest inter-core skew per span on the link. Furthermore, we show that with inter-core skew compensation, the required memory length of the SDM-MIMO is nearly constant with the transmission distance for accumulated crosstalk below -11 dB. We experimentally demonstrate the use of SDM-MIMO with a memory length of 20 ns on a long distance transmission link using 20 GBaud PDM-QPSK signals. We achieve a reach of 9780 km, which corresponds to a 9% improvement over the case without SDM-MIMO. We also show that the use of SDM-MIMO is applicable to the transmission of signals with higher modulation order, achieving transmission reach improvements of 14% for 20 GBaud PDM-16QAM and PDM-64QAM signals.

Volume holographic spatial mode demultiplexer with a dual-wavelength method.

Volume holographic demultiplexers (VHDMs) provide spatial mode demultiplexing using simple optical systems. However, applying VHDM to practical optical communication systems is difficult, as typical holographic media have no sensitivity in the infrared region, which includes optical transmission bands. In this paper, we propose a VHDM scheme combined with a dual-wavelength method (DWM). Using the DWM, VHDMs are able to perform mode demultiplexing in the optical transmission bands. We experimentally demonstrated the basic operation of our proposal using experiments performed at an 850-nm wavelength. In addition, we performed numerical simulations to investigate the application of VHDM to the C-band.

Few-mode fiber, splice and SDM component characterization by spatially-diverse optical vector network analysis.

This paper discusses spatially diverse optical vector network analysis for space division multiplexing (SDM) component and system characterization, which is becoming essential as SDM is widely considered to increase the capacity of optical communication systems. Characterization of a 108-channel photonic lantern spatial multiplexer, coupled to a 36-core 3-mode fiber, is experimentally demonstrated, extracting the full impulse response and complex transfer function matrices as well as insertion loss (IL) and mode-dependent loss (MDL) data. Moreover, the mode-mixing behavior of fiber splices in the few-mode multi-core fiber and their impact on system IL and MDL are analyzed, finding splices to cause significant mode-mixing and to be non-negligible in system capacity analysis.

Crosstalk dynamics in multi-core fibers.

Inter-core crosstalk is a potential limitation on the achievable data-rates in optical fiber transmission systems using multi-core fibers. Crosstalk arises from unwanted coupling between cores of a homogenous multi-core fiber and it's average power has been observed to vary over time by 10s of decibels, potentially requiring an additional performance margin to achieve acceptable outage probability. Most investigations of crosstalk have so far only considered continuous wave laser light or amplified spontaneous emission as sources of crosstalk. In this paper, we theoretically and experimentally investigate the time-dependence of inter-core crosstalk in a homogeneous multi-core fiber when considering signals with various modulation formats and symbol rates. We find that crosstalk power fluctuations depend on the symbol rate, modulation and skew between cores. For carrier-free signals, such as quadrature amplitude modulation, the crosstalk power is nearly constant for expected conditions of multi-core transmission systems. However, carrier-supported signals, such as OOK, always induce time-varying crosstalk powers.

Performance of adaptive DD-OFDM multicore fiber links and its relation with intercore crosstalk.

Adaptive direct-detection (DD) orthogonal frequency-division multiplexing (OFDM) is proposed to guarantee signal quality over time in weakly-coupled homogenous multicore fiber (MCFs) links impaired by stochastic intercore crosstalk (ICXT). For the first time, the received electrical power of the ICXT and the performance of the adaptive DD-OFDM MCF link are experimentally monitored quasi-simultaneously over a 210 hour period. Experimental results show that the time evolution of the error vector magnitude due to the ICXT can be suitably estimated from the normalized power of the detected crosstalk. The detected crosstalk results from the beating between the carrier in the test core and ICXT originating from the carrier and modulated signal from interfering core. The results show that the operation of DD-OFDM systems employing fixed modulation can be severely impaired by the presence of ICXT that may unpredictable vary in both power and frequency. The system may suffer from deleterious impact of moderate ICXT levels over a time duration of several hours or from peak ICXT levels occurring over a number of minutes. Such power fluctuations can lead to large variations in bit error ratio (BER) for static modulation schemes. Here, we show that BER fluctuations may be minimized by the use of adaptive modulation techniques and that in particular, the adaptive OFDM is a viable solution to guarantee link quality in MCF-based systems. An experimental model of an adaptive DD-OFDM MCF link shows an average throughput of 12 Gb/s that represents a reduction of only 9% compared to the maximum throughput measured without ICXT and an improvement of 23% relative to throughput obtained with static modulation.

All-optical Nyquist-OTDM to Nyquist-WDM conversion for high-granular flexible optical networks.

We have proposed and experimentally demonstrated all-optical multiplexing (MUX)-format conversion from Nyquist optical time division multiplex (OTDM) to Nyquist wavelength division multiplex (WDM). The system is simply configured with a straight-type phase modulator (PM) driven by a sinusoidal wave and an optical Nyquist filter. In the theoretical investigation, it is proved that the single Nyquist signal is completely converted to Nyquist WDM signal, which consists of two half-baud-rate signals with different carrier frequencies. The theoretical modulation voltage for the phase modulator is slightly lower than Vπ: 0.913 Vπ, and it is experimentally verified. In the experimental demonstrations, 50 Gbaud to 25 Gbaud x 2 and 25 Gbaud to 12.5 Gbaud x 2 conversions are successfully demonstrated with quite low optical signal-to-noise ratio (OSNR) penalties. In addition, cascaded MUX-format conversion is also demonstrated; 50 Gbaud Nyquist signal is converted to four channels of 12.5 Gbaud Nyquist signals.

Effect of water-immersion restraint stress on tryptophan catabolism through the kynurenine pathway in rat tissues.

The aim of this study was to clarify the effect of water-immersion restraint stress (WIRS) on tryptophan (Trp) catabolism through the kynurenine (Kyn) pathway in rat tissues. The tissues of rats subjected to 6 h of WIRS (+WIRS) had increased tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) activities and increased TDO and IDO1 (one of two IDO isozymes in mammals) mRNA expression levels, with decreased Trp and increased Kyn contents in the liver. +WIRS rats had unchanged TDO and IDO activities in the kidney, decreased TDO activity and unchanged IDO activity in the brain, and unchanged IDO activity in the lung and spleen, with increased Kyn content in all of these tissues. Pretreatment of stressed rats with RU486, a glucocorticoid antagonist, attenuated the increased TOD activity, but not the increased IDO activity, with partial recoveries of the decreased Trp and increased Kyn contents in the liver. These results indicate that WIRS enhances hepatic Trp catabolism by inducing both IDO1 and TDO in rats.

Pump-phase-noise-free optical wavelength data exchange between QAM signals with 50-GHz channel-spacing using coherent DFB pump.

An important challenge for implementing optical signal processing functions such as wavelength conversion or wavelength data exchange (WDE) is to avoid the introduction of linear and nonlinear phase noise in the subsystem. This is particularly important for phase noise sensitive, high-order quadrature-amplitude modulation (QAM) signals. In this paper, we propose and experimentally demonstrate an optical data exchange scheme through cascaded 2nd-order nonlinearities in periodically-poled lithium niobate (PPLN) waveguides using coherent pumping. The proposed coherent pumping scheme enables noise from the coherent pumps to be cancelled out in the swapped data after WDE, even with broad linewidth distributed feedback (DFB) pump lasers. Hence, this scheme allows phase noise tolerant processing functions, enabling the low-cost implementation of WDE for high-order QAM signals. We experimentally demonstrate WDEs between 10-Gbaud 4QAM (4QAM) signal and 12.5-Gbaud 4QAM (16QAM) signal with 3.5-MHz linewidth DFB pump lasers and 50-GHz channel spacing. Error-free operation is observed for the swapped QAM signals with coherent DFB pumping whilst use of free-running DFB pumps leads to visible error floors and unrecoverable phase errors. The phase noise cancellation in the coherent pump scheme is further confirmed by study of the recovered carrier phase of the converted signals. In addition to pump phase noise, the influence of crosstalk caused by the finite extinction ratio in WDE is also experimentally investigated for the swapped QAM signals.