DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Survival Outcomes of Patients with Esophageal Cancer and Post-chemoradiotherapy Surgical T4b Disease: Is Palliative Resection Justified?

BACKGROUND: In patients with locally advanced esophageal cancer who had undergone chemoradiotherapy (CRT), the limitations of radiological evaluation may necessitate surgical exploration to ascertain disease resectability. Upon intraoperative confirmation of T4b disease (sT4b), the optimal management strategy remains unclear. While some surgeons may opt against resection, others advocate for palliative esophagectomy (PE). Regrettably, the current literature does not provide a consensus on the most effective approach for managing these intricate cases. METHODS: The study cohort consisted of 68 patients with esophageal squamous cell carcinoma (ESCC) who presented with sT4b disease following CRT. The perioperative outcomes and overall survival (OS) were compared between patients who underwent PE (n = 56) and those who received an open-close (OC) procedure (n = 12). RESULTS: Patients who underwent an OC procedure experienced a shorter hospital stay (16.5 vs. 28.8 days; p = 0.052) and showed a non-significant reduction in the rate of major complications (33.9% vs. 25%; p = 0.549) and in-hospital mortality (0% vs. 5.4%; p = 0.412) than those who received PE; however, PE was associated with a superior 2-year OS rate than OC (9.6% vs. 0%; p = 0.009). In multivariable analysis, a pretreatment clinical stage of II/III (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.31-0.87; p = 0.013) and PE with retrosternal reconstruction (HR 0.38, 95% CI 0.15-0.49; p = 0.010) were independently associated with a more favorable OS. CONCLUSION: PE with retrosternal reconstruction may be a feasible approach for patients with ESCC exhibiting sT4b disease after CRT.

Impact of Weekend Effect on Short- and Long-Term Survival of Patients Undergoing Esophagectomy for Cancer: A Population-Based, Inverse Probability of Treatment-Weighted Analysis.

BACKGROUND: We examined the impact of the weekend effect on the survival outcomes of patients undergoing elective esophagectomy for cancer. METHODS: This was a retrospective analysis of a nationwide, health administrative dataset that included all patients (n = 3235) who had undergone elective esophagectomy for cancer in Taiwanese hospitals between 2008 and 2015. Patients were categorized according to the day of surgery (weekday group: surgical procedures starting Monday through Friday, n = 3148; weekend group: surgical procedures starting on Saturday or Sunday, n = 87). Inverse probability of treatment weighting (IPTW) using the propensity score was used to account for selection bias due to baseline differences. RESULTS: After IPTW, patients undergoing esophagectomy on weekends had a higher 90-days mortality rate compared with those undergoing surgery on a weekday (10.5% vs. 5.5%, respectively, P < 0.001). After controlling for potential confounders, weekend surgery was identified as an independent adverse predictor of 2-years, overall survival [hazard ratio (HR) = 1.38, P < 0.001]. Importantly, inferior weekend outcomes were especially evident in certain subgroups, including patients aged > 60 years (HR = 1.61, P < 0.001), as well as those with a high burden of comorbidities (HR = 1.32, P < 0.001), advanced tumor stage (HR = 1.50, P < 0.001), histological diagnosis of squamous cell carcinoma (HR = 1.20, P < 0.001), and treated with minimally invasive esophagectomy (HR = 1.26, P < 0.001). CONCLUSIONS: Elective esophagectomy for cancer during weekends has an adverse impact on short- and long-term survival.

Treatment burden and cost-effectiveness analysis of the neoadjuvant CROSS regimen in esophageal squamous cell carcinoma: a multicenter retrospective study.

High-quality evidence indicated that both neoadjuvant carboplatin/paclitaxel (CROSS) and cisplatin/5-fluorouracil (PF) regimens in combination with radiotherapy improve survival outcomes compared to surgery alone in patients with esophageal cancer. It is not yet known whether they may differ in terms of treatment burden and healthcare costs. A total of 232 Taiwanese patients with esophageal squamous cell carcinoma who had undergone neoadjuvant chemoradiotherapy (nCRT) with either the CROSS (n = 153) or the PF (n = 79) regimens were included. Hospital encounters and adverse events were assessed for determining treatment burden. Cost-effectiveness analysis was undertaken using the total costs incurred over 3 years in relation to overall survival (OS) and progression-free survival (PFS). Compared with PF, the CROSS regimen was associated with a lower treatment burden: shorter inpatient days on average (4.65 ± 10.05 vs. 15.14 ± 17.63 days; P < 0.001) and fewer admission requirements (70% of the patients were never admitted vs. 20% in the PF group; P < 0.001). Patients in the CROSS group experienced significantly less nausea, vomiting, and diarrhea. While the benefits observed in the CROSS group were associated with additional nCRT-related expenditures (1388 United States dollars [USD] of added cost per patient), this regimen remained cost-effective. At a willingness-to-pay threshold of 50,000 USD per life-year, the probability of the CROSS regimen to be more cost-effective than PF was 94.1% for PFS but decreased to 68.9% for OS. The use of the CROSS regimen for nCRT in patients with ESCC was associated with a lower treatment burden and was more cost-effective than PF.

Shape-controlled single-crystal growth of InP at low temperatures down to 220 °C.

III-V compound semiconductors are widely used for electronic and optoelectronic applications. However, interfacing III-Vs with other materials has been fundamentally limited by the high growth temperatures and lattice-match requirements of traditional deposition processes. Recently, we developed the templated liquid-phase (TLP) crystal growth method for enabling direct growth of shape-controlled single-crystal III-Vs on amorphous substrates. Although in theory, the lowest temperature for TLP growth is that of the melting point of the group III metal (e.g., 156.6 °C for indium), previous experiments required a minimum growth temperature of 500 °C, thus being incompatible with many application-specific substrates. Here, we demonstrate low-temperature TLP (LT-TLP) growth of single-crystalline InP patterns at substrate temperatures down to 220 °C by first activating the precursor, thus enabling the direct growth of InP even on low thermal budget substrates such as plastics and indium-tin-oxide (ITO)-coated glass. Importantly, the material exhibits high electron mobilities and good optoelectronic properties as demonstrated by the fabrication of high-performance transistors and light-emitting devices. Furthermore, this work may enable integration of III-Vs with silicon complementary metal-oxide-semiconductor (CMOS) processing for monolithic 3D integrated circuits and/or back-end electronics.

Tuberculous peritonitis in patients on peritoneal dialysis: a 35-year experience from a large medical center in Northern Taiwan.

INTRODUCTION: Tuberculous peritonitis (TBP) is a rare but fatal complication in patients on peritoneal dialysis (PD). In this study, we aimed to determine the demographic features, clinical features, laboratory parameters, and clinical outcomes of PD patients with TBP and to clarify possible risk factors for mortality. MATERIALS AND METHODS: We retrospectively reviewed 2084 PD patients from January 1985 to December 2019. The diagnosis of TBP was established by positive peritoneal fluid culture for Mycobacterium tuberculosis. RESULTS: 18 patients were diagnosed with TBP. The incidence was 2.029 episodes per 1000 patient-years. The most common symptom was fever (94.4%), followed by cloudy effluent (83.3%) and abdominal pain (83.3%). The average peritoneal dialysis effluent (PDE) white blood cell (WBC) count was 172.7 cells/µL. Nine patients (50%) had WBC counts lower than 100 cells/µL and 13 patients (72.2%) had neutrophilic predominant WBC counts. Acid fast stain (AFS) was positive in 7 patients (38.9%). Only 2 patients (11.1%) continued with PD after TB infection, while 10 patients (55.6%) changed to hemodialysis. Seven patients (38.9%) died within 1 year. Significant differences were observed in sex (p = 0.040), the presence of diabetes mellitus (p = 0.024), and PD catheter removal (p < 0.001) between TBP patients with and without mortality. However, none of them was a significant factor for 1-year mortality in multivariate Cox regression model. CONCLUSION: Physicians should pay attention to the unusual presentations of peritonitis, especially if symptoms include fever or an initial low PDE WBC count. Catheter removal is not mandatory if early diagnosis and appropriate therapy are available.

Global phosphoproteomic profiling of skeletal muscle in ovarian hormone-deficient mice.

Protein phosphorylation is important in skeletal muscle development, growth, regeneration, and contractile function. Alterations in the skeletal muscle phosphoproteome due to aging have been reported in males; however, studies in females are lacking. We have demonstrated that estrogen deficiency decreases muscle force, which correlates with decreased myosin regulatory light chain phosphorylation. Thus, we questioned whether the decline of estrogen in females that occurs with aging might alter the skeletal muscle phosphoproteome. C57BL/6J female mice (6 mo) were randomly assigned to a sham-operated (Sham) or ovariectomy (Ovx) group to investigate the effects of estrogen deficiency on skeletal muscle protein phosphorylation in a resting, noncontracting condition. After 16 wk of estrogen deficiency, the tibialis anterior muscle was dissected and prepped for label-free nano-liquid chromatography-tandem mass spectrometry phosphoproteomic analysis. We identified 4,780 phosphopeptides in tibialis anterior muscles of ovariectomized (Ovx) and Sham-operated (Sham) control mice. Further analysis revealed 647 differentially regulated phosphopeptides (Benjamini-Hochberg adjusted P value < 0.05 and 1.5-fold change ratio) that corresponded to 130 proteins with 22 proteins differentially phosphorylated (3 unique to Ovx, 2 unique to Sham, 6 upregulated, and 11 downregulated). Differentially phosphorylated proteins associated with the sarcomere, cytoplasm, and metabolic and calcium signaling pathways were identified. Our work provides the first global phosphoproteomic analysis in females and how estrogen deficiency impacts the skeletal muscle phosphoproteome.

Multifunctional Ion-Sensitive Floating Gate Fin Field-Effect Transistor with Three-Dimensional Nanoseaweed Structure by Glancing Angle Deposition Technology.

A multifunctional ion-sensitive floating gate Fin field-effect transistor (ISFGFinFET) for hydrogen and sodium detection is demonstrated. The ISFGFinFET comprises a FGFET and a sensing film, both of which are used to detect and improve sensitivity. The sensitivity of the ISFGFinFET can be adjusted by modulating the coupling effect of the FG. A nanoseaweed structure is fabricated via glancing angle deposition (GLAD) technology to obtain a large sensing area to enhance the sensitivity for hydrogen ion detection. A sensitivity of 266 mV per pH can be obtained using a surface area of 3.28 mm2 . In terms of sodium ion detection, a calix[4]arene sensing film to monitor sodium ions, obtaining a Na+ sensitivity of 432.7 mV per pNa, is used. In addition, the ISFGFinFET demonstrates the functionality of multiple ions detection simultaneously. The sensor arrays composed of 3 × 3 pixels are demonstrated, each of which comprise of an FGFET sensor and a transistor. Furthermore, 16 × 16 arrays with a decoder and other peripheral circuits are constructed and simulated. The performance of the proposed ISFGFinFET is competitive with that of other state-of-the-art ion sensors.

Longer charged amino acids favor ß-strand formation in hairpin peptides.

Interactions between charged amino acids significantly influence the structure and function of proteins. The encoded charged amino acids Asp, Glu, Arg, and Lys have different number of hydrophobic methylenes linking the backbone to the charged functionality. It remains to be fully understood how does this difference in the number of methylenes affect protein structure stability. Protein secondary structures are the fundamental three-dimensional building blocks of protein structures. ß-Sheet structures are particularly interesting, because these structures have been associated with a number of protein misfolding diseases. Herein, we report the effect of charged amino acid side chain length at two ß-strand positions individually on the stability of a ß-hairpin. The charged amino acids include side chains with a carboxylate, an ammonium, or a guanidinium group. The experimental peptides, fully folded reference peptides, and fully unfolded reference peptides were synthesized by solid phase peptide synthesis and analyzed by 2D NMR methods including TOCSY, DQF-COSY, and ROESY. Sequence specific assignments were performed for all peptides. The chemical shift data were used to derive the fraction folded population and the folding free energy for the experimental peptides. Results showed that the fraction folded population increased with increasing charged amino acid side chain length. These results should be useful for developing functional peptides that adopt the ß-conformation.

Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.

Resistance to chemotherapy can occur through a wide variety of mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often arises from kinase mutations-however, "off-target" resistance occurs but is poorly understood. Previously, we established cell line resistance models for three TKIs used in chronic myeloid leukemia treatment, and found that resistance was not attributed entirely to failure of kinase inhibition. Here, we performed global, integrated proteomic and transcriptomic profiling of these cell lines to describe mechanisms of resistance at the protein and gene expression level. We used whole transcriptome sequencing and SWATH-based data-independent acquisition mass spectrometry (DIA-MS), which does not require isotopic labels and provides quantitative measurements of proteins in a comprehensive, unbiased fashion. The proteomic and transcriptional data were correlated to generate an integrated understanding of the gene expression and protein alterations associated with TKI resistance. We defined mechanisms of resistance and two novel markers, CA1 and alpha-synuclein, that were common to all TKIs tested. Resistance to all of the TKIs was associated with oxidative stress responses, hypoxia signatures, and apparent metabolic reprogramming of the cells. Metabolite profiling and glucose-dependence experiments showed that resistant cells had routed their metabolism through glycolysis (particularly through the pentose phosphate pathway) and exhibited disruptions in mitochondrial metabolism. These experiments are the first to report a global, integrated proteomic, transcriptomic, and metabolic analysis of TKI resistance. These data suggest that although the mechanisms are complex, targeting metabolic pathways along with TKI treatment may overcome pan-TKI resistance.

Enhanced Photocarrier Generation with Selectable Wavelengths by M-Decorated-CuInS2 Nanocrystals (M = Au and Pt) Synthesized in a Single Surfactant Process on MoS2 Bilayers.

A facile approach for the synthesis of Au- and Pt-decorated CuInS2 nanocrystals (CIS NCs) as sensitizer materials on the top of MoS2 bilayers is demonstrated. A single surfactant (oleylamine) is used to prepare such heterostructured noble metal decorated CIS NCs from the pristine CIS. Such a feasible way to synthesize heterostructured noble metal decorated CIS NCs from the single surfactant can stimulate the development of the functionalized heterostructured NCs in large scale for practical applications such as solar cells and photodetectors. Photodetectors based on MoS2 bilayers with the synthesized nanocrystals display enhanced photocurrent, almost 20-40 times higher responsivity and the On/Off ratio is enlarged one order of magnitude compared with the pristine MoS2 bilayers-based photodetectors. Remarkably, by using Pt- or Au-decorated CIS NCs, the photocurrent enhancement of MoS2 photodetectors can be tuned between blue (405 nm) to green (532 nm). The strategy described here acts as a perspective to significantly improve the performance of MoS2 -based photodetectors with the controllable absorption wavelengths in the visible light range, showing the feasibility of the possible color detection.

Dynamic effect of economic growth on the persistence of suicide rates.

Positive and negative economic growth is closely related to the suicide rate. To answer the question whether economic development has a dynamic impact on this rate, we used a panel smooth transition autoregressive model to evaluate the threshold effect of economic growth rate on the persistence of suicide. The research period was from 1994 to 2020, and the results show that the suicide rate had a persistent effect, which varied over time depending on the transition variable within different threshold intervals. However, the persistent effect was manifested in different degrees with the change in the economic growth rate and as the lag period of the suicide rate increased, the effect of the influence gradually decreased. We investigated different lag periods and noted that the impact on the suicide rate was the strongest in the first year after an economic change and then reduced to be only marginal after three years. This means that the growth momentum of the suicide rate within the first two years after a change in the economic growth rate, should be included in policy considerations of how to prevent suicides.

Natural aging and ovariectomy induces parallel phosphoproteomic alterations in skeletal muscle of female mice.

The loss of skeletal muscle strength mid-life in females is associated with the decline of estrogen. Here, we questioned how estrogen deficiency might impact the overall skeletal muscle phosphoproteome after contraction, as force production induces phosphorylation of several muscle proteins. Phosphoproteomic analyses of the tibialis anterior muscle after contraction in two mouse models of estrogen deficiency, ovariectomy (Ovariectomized (Ovx) vs. Sham) and natural aging-induced ovarian senescence (Older Adult (OA) vs. Young Adult (YA)), identified a total of 2,593 and 3,507 phosphopeptides in Ovx/Sham and OA/YA datasets, respectively. Further analysis of estrogen deficiency-associated proteins and phosphosites identified 66 proteins and 21 phosphosites from both datasets. Of these, 4 estrogen deficiency-associated proteins and 4 estrogen deficiency-associated phosphosites were significant and differentially phosphorylated or regulated, respectively. Comparative analyses between Ovx/Sham and OA/YA using Ingenuity Pathway Analysis (IPA) found parallel patterns of inhibition and activation across IPA-defined canonical signaling pathways and physiological functional analysis, which were similarly observed in downstream GO, KEGG, and Reactome pathway overrepresentation analysis pertaining to muscle structural integrity and contraction, including AMPK and calcium signaling. IPA Upstream regulator analysis identified MAPK1 and PRKACA as candidate kinases and calcineurin as a candidate phosphatase sensitive to estrogen. Our findings highlight key molecular signatures and pathways in contracted muscle suggesting that the similarities identified across both datasets could elucidate molecular mechanisms that may contribute to skeletal muscle strength loss due to estrogen deficiency.

Phase/Interfacial-Engineered Two-Dimensional-Layered WSe2 Films by a Plasma-Assisted Selenization Process: Modulation of Oxygen Vacancies in Resistive Random-Access Memory.

Here, we propose phase and interfacial engineering by inserting a functional WO3 layer and selenized it to achieve a 2D-layered WSe2/WO3 heterolayer structure by a plasma-assisted selenization process. The 2D-layered WSe2/WO3 heterolayer was coupled with an Al2O3 film as a resistive switching (RS) layer to form a hybrid structure, with which Pt and W films were used as the top and bottom electrodes, respectively. The device with good uniformity in SET/RESET voltage and high low-/high-resistance window can be obtained by controlling a conversion ratio from a WO3 film to a 2D-layered WSe2 thin film. The Pt/Al2O3/(2D-layered WSe2/WO3)/W structure shows remarkable improvement to the pristine Pt/Al2O3/W and Pt/Al2O3/2D-layered WO3/W in terms of low SET/RESET voltage variability (-20/20)%, multilevel characteristics (uniform LRS/HRS distribution), high on/off ratio (104-105), and retention (∼105 s). The thickness of the obtained WSe2 was tuned at different gas ratios to optimize different 2D-layered WSe2/WO3 (%) ratios, showing a distinctive trend of reduced and uniform SET/RESET voltage variability as 2D-layered WSe2/WO3 (%) changes from 90/10 (%) to 45/55 (%), respectively. The electrical measurements confirm the superior ability of the metallic 1T phase of the 2D-layered WSe2 over the semiconducting 2H phase. Through systemic studies of RS behaviors on the effect of 1T/2H phases and 2D-layered WSe2/WO3 ratios, the low-temperature plasma-assisted selenization offers compatibility with the temperature-limited 3D integration process and also provides much better thickness control over a large area.

Rational Design on Polymorphous Phase Switching in Molybdenum Diselenide-Based Memristor Assisted by All-Solid-State Reversible Intercalation toward Neuromorphic Application.

In this work, a low-power memristor based on vertically stacked two-dimensional (2D) layered materials, achieved by plasma-assisted vapor reaction, as the switching material, with which the copper and gold metals as electrodes featured by reversible polymorphous phase changes from a conducting 1T-phase to a semiconducting 2H-one once copper cations interacted between vertical lamellar layers and vice versa, was demonstrated. Here, molybdenum diselenide was chosen as the switching material, and the reversible polymorphous phase changes activated by the intercalation of Cu cations were confirmed by pseudo-operando Raman scattering, transmission electron microscopy, and scanning photoelectron microscopy under high and low resistance states, respectively. The switching can be activated at about ±1 V with critical currents less than 10 µA with an on/off ratio approaching 100 after 100 cycles and low power consumption of ∼0.1 microwatt as well as linear weight updates controlled by the amount of intercalation. The work provides alternative feasibility of reversible and all-solid-state metal interactions, which benefits monolithic integrations of 2D materials into operative electronic circuits.