NIR-responsive CN-Pt-GEM hydrogel induces necroptosis and immunotherapeutic responses prevent postoperative recurrence and wound infection in lung carcinoma.

BACKGROUND: Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse. RESULTS: The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection. CONCLUSIONS: These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

ROS-induced translational regulation-through spatiotemporal differences in codon recognition-is a key driver of brown adipogenesis.

The role of translational regulation in brown adipogenesis is relatively unknown. Localized translation of mRNAs encoding mitochondrial components enables swift mitochondrial responses, but whether this occurs during brown adipogenesis, which involves massive mitochondrial biogenesis, has not been explored. Here, we used ribosome profiling and RNA-Seq, coupled with cellular fractionation, to obtain spatiotemporal insights into translational regulation. During brown adipogenesis, a translation bias towards G/C-ending codons is triggered first in the mitochondrial vicinity by reactive oxygen species (ROS), which later spreads to the rest of the cell. This translation bias is induced through ROS modulating the activity of the tRNA modification enzyme, ELP3. Intriguingly, functionally relevant mRNAs, including those encoding ROS scavengers, benefit from this bias; in so doing, ROS-induced translation bias both fuels differentiation and concurrently minimizes oxidative damage. These ROS-induced changes could enable sustained mitochondrial biogenesis during brown adipogenesis, and explain in part, the molecular basis for ROS hormesis.

A novel location classification system for Crohn's disease based on small bowel involvement: a better predictor of disease progression.

Background: Small bowel involvement is related to poor prognosis in Crohn's disease (CD), which may be a potential marker to stratify patients with a high risk of progression. This study aimed to establish a novel location classification system for CD and to develop a predictive model for disease progression. Methods: Consecutive patients with non-stricturing/non-penetrating CD were retrospectively included in the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, P. R. China) between January 2012 and January 2018. Patients were classified into two groups according to disease location: small bowel involvement group and isolated colon group. The primary outcome was disease progression to stricturing or penetrating phenotypes. Progression-free survival was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. Results: A total of 463 patients were analysed, with a median follow-up time of 55.3 months. Patients with small bowel involvement had a higher risk of disease progression than those with isolated colon disease (hazard ratio = 1.998, P = 0.007), while no differences were found between Montreal location classification and disease progression. Median progression-free survival was higher in the isolated colon group than in the small bowel involvement group (84.5 vs 77.3 months, P = 0.006). Four independent factors associated with disease progression were identified: small bowel involvement, duration of onset of >1 year, deep mucosal ulcer, and C-reactive protein levels of ≥10 mg/L (all P < 0.05). The nomogram model based on these factors showed good performance in predicting disease progression, with a C-index of 0.746 (95% confidence interval, 0.707-0.785). Conclusions: Classifying CD based on small bowel involvement and isolated colon was superior to the Montreal location classification for predicting disease progression.

Polysomnographic features of insomnia occurring in major depressive disorder, generalized anxiety disorder and bipolar mania: Comparison with primary insomnia and association with metabolic indicators.

BACKGROUND: Insomnia is very common in psychiatric disorders, but the polysomnographic (PSG) characteristics of insomnia in various psychiatric disorders are still not agreed upon. This study aimed to investigate the characteristics of PSG and its relationship with metabolic indicators in insomnia patients with affective disorders and primary insomnia (PI) patients. METHODS: A total of 38 patients with PI, 44 major depressive disorder patients with insomnia (DI), 49 generalized anxiety disorder patients with insomnia (GI), and 19 bipolar mania patients with insomnia (BI) were included. PSG was used to detect sleep problems in subjects, and biochemical indicators were also collected. RESULTS: The results of this study found that subjects with BI were lower on REM sleep latency (RL), awakenings number (AN), number of microarousals (NM), and apnea-hypopnea index (AHI) than those with DI and GI, and lower on RL and AN than those with PI. Subjects with PI had lower NM and AHI than those with DI and GI. Patients with DI had a higher RL than those with GI. All results passed Bonferroni correction (p < 0.00078). No differences in biochemical indices were found among the four groups of subjects. Also, AHI was found to be positively correlated with free triiodothyronine (FT3) and fasting blood glucose in subjects. CONCLUSION: This study suggests that various psychiatric disorders may have their characteristics in terms of PSG parameters, which prompted us to focus on the PSG characteristics of these disorders when assessing them, as well as to focus on their biochemical indicators.

Altered orientation dispersion index of white matter in individuals with insomnia during the COVID-19 pandemic: A study combining neuroimaging technique and Mendelian randomization.

STUDY OBJECTIVES: Coronavirus disease 2019 (COVID-19) can lead to insomnia. However, associations between COVID-19-caused insomnia and white matter (WM) changes are unclear. METHODS: All subjects had ever been infected with COVID-19. We investigated 89 insomniacs (29 chronic insomniacs, 33 new-onset insomniacs, 27 aggravated insomniacs) and 44 matched non-insomnia participants. Neurite orientation dispersion and density imaging (NODDI) was performed to identify micro-structural alterations of WM, and twelve scales related to sleeping status, memory, attention, learning, emotional status, and executive functions were used. Then, correlations between insomnia/cognitive-behavioral functions and diffusion metrics were tested. To eliminate influence of pre-COVID-19 factors on insomnia, causal relationships between COVID-19 and WM changes were validated by Mendelian randomization (MR) analysis. The significant brain regions of COVID-19-caused insomnia were intersected results of tract-based spatial statistics (TBSS) and MR analyses. RESULTS: Compared to non-insomnia group, insomnia group and its subgroups including post-COVID-19 aggravated or unchanged chronic insomnia group had higher orientation dispersion index (ODI) in extensive brain regions. The left superior longitudinal fasciculus (SLF), left posterior thalamic radiation (PTR), and left cingulate gyrus (CG) were specific brain regions in COVID-19-induced insomnia aggravation. After Bonferroni correction, partial correlation analyses within insomnia group showed that ODI in left SLF was positively correlated with Pittsburgh sleep quality index (PSQI), insomnia severity index (ISI), and self-rating anxiety scale (SAS) scores; ODI in the left PTR was positively correlated with PSQI and ISI scores. CONCLUSIONS: This study is a continuation of our previous research, which provided potential biomarkers for COVID-19-induced insomnia.

Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B.

BACKGROUND & AIMS: HBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for functional cure of CHB can aid in identifying individuals who would benefit from peginterferon-α (Peg-IFNα) therapy. METHODS: We conducted a genome-wide association study (GWAS) by enrolling 48 patients with CHB who achieved HBsAg loss after Peg-IFNα treatment and 47 patients who didn't. In the validation stage, we included 224 patients, of whom 90 had achieved HBsAg loss, to validate the identified significant single nucleotide polymorphisms. To verify the functional involvement of the candidate genes identified, we performed a series of in vitro and in vivo experiments. RESULTS: GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in patients with CHB after Peg-IFNα treatment (p = 4.85 × 10-8, odds ratio = 14.47). This association was also observed in two independent validation cohorts. Expression quantitative trait locus analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (p = 2.90 × 10-6). RNA-sequencing of liver biopsies from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 levels were significantly higher in the HBsAg loss group compared to the HBsAg persistence group (p = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated gene levels and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling. CONCLUSION: The rs7519753 C allele is associated with elevated hepatic TP53BP2 expression and an increased probability of serum HBsAg loss post-Peg-IFNα treatment in patients with CHB. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression. IMPACT AND IMPLICATIONS: Chronic hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in patients with CHB undergoing Peg-IFNα treatment. This finding not only provides a promising predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders based on their potential clinical implications.

Assembly of Lanthanide-Containing 3D [MnMo9O32]6--Based Metal-Organic Frameworks and Oxidative Desulfurization Performance.

Lanthanide-containing polyoxometalate-based metal-organic frameworks (POMOFs) not only enjoy intriguing architectures but also have good application prospects as catalysts. Herein, three novel three-dimensional (3D) POMOFs with the formulas of {H[Ln3(2,6-pydc)2(H2O)10(MnMo9O32)]·2H2O}n (Ln = La(1), Pr(2), Nd(3)) have been synthesized based on Waugh-type [MnMo9O32]6- anions and pyridine-2,6-dicarboxylate (2,6-H2pydc). Compounds 1-3 are isomorphic, and there are two kinds of one-dimensional (1D) helical chains with opposite handedness staggered into two-dimensional (2D) layers. Interestingly, the coordinated L- and R-[MnMo9O32]6- anions are encapsulated in 1D chains with the same chirality and are further expanded into 3D structures. The catalytic tests indicate that compounds 1-3 exhibit high-efficiency heterogeneous catalytic activity in the oxidative desulfurization reaction for catalyzing the oxidation of sulfides to sulfoxides using tert-butyl hydrogen peroxide (TBHP) as the oxidant. Moreover, a series of control experiments have been conducted to investigate the influence of various parameters such as temperature, time, solvent, catalyst, and substrate on the reaction. Significantly, compound 2, as an example, exhibits good reusability and structural stability in the oxidative desulfurization reaction. It is worth noting that investigations on the oxidative desulfurization of [MnMo9O32]6- anions are scarce. Moreover, their electrochemical properties are also explored.

An iRGD-conjugated photothermal therapy-responsive gold nanoparticle system carrying siCDK7 induces necroptosis and immunotherapeutic responses in lung adenocarcinoma.

Although immunotherapy has improved the clinical treatment of lung adenocarcinoma (LUAD), many tumors have poor responses to immunotherapy. In this study, we confirmed that high expression of Cyclin-Dependent Kinase 7 (CDK7) promoted an immunosuppressive macrophage phenotype and macrophage infiltration in LUAD. Thus, we have developed an internalizing-RGD (iRGD)-conjugated gold nanoparticle (AuNP) system which carries siCDK7 to activate the antitumor immune response. The iRGD-conjugated AuNP/siCDK7 system exhibited good tumor targeting performance and photothermal effects. The AuNP/siCDK7 system with excellent biosafety exerted a significant photothermal antitumor effect by inducing tumor cell necroptosis. Furthermore, the AuNP/siCDK7 system ameliorated the immunosuppressive microenvironment and enhanced the efficacy of anti-PD-1 treatment by increasing CD8+ T cell infiltration and decreasing M2 macrophage infiltration. Hence, this iRGD-conjugated AuNP/siCDK7 system is a potential treatment strategy for lung adenocarcinoma, which exerts its effects by triggering tumor cell necroptosis and immunotherapeutic responses.

Neutrophil-to-lymphocyte ratio for predicting postoperative recurrence in Crohn's disease patients with isolated anastomotic lesions.

Background: Patients with isolated anastomotic lesions (iAL) are common in postoperative Crohn's disease (CD) and have heterogeneous prognosis. Objectives: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in CD patients with iAL. Design: A bicenter retrospective cohort study. Methods: CD patients who received ileocolonic resection from 2013 and 2020 and had a modified Rutgeerts score of i2a were recruited. NLR was determined within 1 week around the initial endoscopy after ileocolectomy. The primary outcome was clinical recurrence. Kaplan-Meier method and Cox hazard regression analysis were utilized to assess the association between candidate variables and outcomes of interest. Results: In total, 411 postoperative CD patients were preliminarily reviewed and 83 patients were eligible. In total, 36 (48.6%) patients experienced clinical recurrence with a median follow-up time of 16.3 (interquartile range, 9.7-26.3) months. NLR > 2.45 and age at surgery >45 years had higher cumulative incidence of clinical recurrence in the Kaplan-Meier analysis. After adjusted for potential confounders, NLR > 2.45 was the only independent risk factor for clinical recurrence, with an adjusted hazard ratio (HR) of 2.88 [95% confidence interval (CI), 1.39-6.00; p = 0.005]. Furthermore, a risk score based on NLR and age at surgery were built to further stratify patients. Compared to those who scored 0, patients with a score of 1 and 2 had an adjusted HR of 2.48 (95% CI, 1.22-5.02) and 6.97 (95% CI, 2.19-22.16) for developing clinical recurrence, respectively. Conclusions: NLR is a promising prognostic biomarker for CD patients with iAL. The utilization of NLR and the risk score to stratify patients may facilitate the personalized management in patients with iAL.

Design and Synthesis of Amphiphilic Catalyst [C16mim]5VW12O40Br and Its Application in Deep Desulfurization with Superior Cyclability at Room Temperature.

Achieving long-term stable deep desulfurization at room temperature and recovering high value-added sulfone products is a challenge at present. Herein, a series of catalysts [Cnmim]5VW12O40Br (CnVW12, 1-alkyl-3-methylimidazolium bromide tungstovanadate, n = 4, 8, 16) were presented for the room temperature catalytic oxidation of dibenzothiophene (DBT) and its derivatives. Factors affecting the reaction process, such as the amount of catalyst, oxidant, and temperature, were systematically discussed. C16VW12 showed higher catalytic performance, and 100% conversion and selectivity could be achieved in 50 min with only 10 mg. The mechanism study showed that the hydroxyl radical was the active radical in the reaction. Benefiting from the "polarity strategy", the sulfone product accumulated after 23 cycles in a C16VW12 system, and the yield and purity were about 84% and 100%, respectively.

An experimental investigation of the erosion process and morphological characteristics of the tile-back type slope with non-uniform slopes based on a 3D reconstruction method.

Tile-back type slopes comprise ephemeral gullies (EGs) and hillslopes; they are a unique and widely distributed micro-landform in the Loess Plateau region of China. Gully erosion from these landforms is a serious issue, but the micro-landform makes the erosion process and its estimation complex. Quantifying soil erosion processes and their distribution characteristics at different positions on tile-back type slopes will provide a clearer picture for ecological restoration to control further soil degradation. This study investigated the erosion process of tile-back type slope with non-uniform slopes using a 3D photo-reconstruction method during eight successive simulated rainfall events. The results showed that EG erosion began with a chain of intermittent headcuts. When the accumulated rainfall reached 76 mm, serious collapses dramatically increased the amount of sediment by 216% after the first rainfall (cumulative rainfall was about 15 mm). We quantified the sediment contribution of EG erosion (46.20%), rill erosion (35.62%), and inter-rill erosion (18.18%) to total soil loss. The erosion area of the steep slope section and extremely steep slope section accounted for 33.26% and 66.74% of the total erosion area, respectively. Moreover, sediment amounts significantly correlated with morphological parameters, particularly the amount of EG erosion and maximum gully depth, with a correlation coefficient of 0.98. Cumulative gully length and erosion area had the greatest effect on rill erosion, with a correlation coefficient of 0.97. These results provide insight into the qualitative and quantitative understanding of EG erosion process on Loess Plateau of China and an important reference for the rational arrangement of EG control measures.

Two three-dimensional Fe(II) frameworks based on {P4Mo6} tetrameric clusters exhibiting efficient visible-light photocatalytic properties for the degradation of Cr(VI) and methylene blue.

Two three-dimensional frameworks based on the {P4Mo6} unit, H(4,4'-bipy)2[Fe4(PO4)(H2O)4Na6][Fe6(H2O)4][(Mo6O12)(HPO4)3(PO4)(OH)3]4·5H2O (4,4'-bipy = 4,4'-bipyridine) (1) and H3(C12H14N2)4[Fe4(PO4)(H2O)4Na4][Fe2(Mo6O12(HPO4)3(PO4)(OH)3)4]·6H2O (2) were successfully synthesized by varying the solvent. The extended structures of the two compounds were formed by transition metal Fe(II) ions bridging the {P4Mo6}-based tetrameric clusters around [NaXFe4(PO4)] (X = 6 (1), or X = 4 (2)) core. The 4,4'-bipy molecules and in situ generated methyl viologen cations as templates induce the formation of two three-dimensional structures, an 8-connected bcu topology framework for 1 and a 4-connected 2-fold interpenetrating diamond-like topological network for 2, respectively. Additionally, multiform hydrogen bonds are found in the framework and also play an important role in stabilizing the structure. The proton conduction mechanism of the two compounds can be mainly classified as the Grotthuss mechanism; the proton conductivity values are 1.06 × 10-3 S cm-1 for 1 and 3.13 × 10-3 S cm-1 for 2 at 75 °C under 98% relative humidity. The visible-light photocatalytic activity was evaluated by photocatalytic decomposition of Cr(VI) and MB dye, and the removal ratios can reach 95.6% (1) and 82% (2) for Cr(VI), and 98% (1) and 99% (2) for MB.

Nanoetching TiO2 nanorod photoanodes to induce high-energy facet exposure for enhanced photoelectrochemical performance.

Crystal facet engineering is considered as an effective way to improve photoelectrochemical (PEC) performance. Here, we have developed a nanoetching technology (TiO2 → TiO2/Bi4Ti3O12 → TiO2/BiVO4 → etching-TiO2) to treat rutile TiO2 nanorod films. Interestingly, the technology can induce the exposure of a large number of high energy (101) faces, and the etching-TiO2 film (E-TiO2) showed a significantly enhanced PEC performance. A dynamic study indicates that charge separation and transfer have been obviously improved by such a nanoetching technology. In particular, the charge transfer efficiency (ηtrans) of E-TiO2 reaches 93.4% at 1.23 V vs. RHE without any loaded cocatalyst. The mechanism of PEC performance enhanced by the strategy is experimentally and theoretically unraveled. The improvement of PEC performance is mainly attributed to the shorter distance between H and the neighboring O-b for the HO* intermediates of the rutile (101) facet, which can reduce the energy barrier for the OER. Besides, the driving force for spatial charge separation between the (110) and (101) facets can promote charge separation. This work offers a new and versatile nanotechnology to induce the exposure of the high energy crystal facets and improve the PEC performance.

A fully automated sex estimation for proximal femur X-ray images through deep learning detection and classification.

PURPOSE: To develop a fully automated deep learning pipeline using digital radiographs to detect the proximal femur region for accurate automated sex estimation. METHOD: Radiograph predictive features from 2122 Chinese Han clinical pelvic with ages ranging from 18 to 26 years were collected retrospectively to train and test the sex prediction model using deep machine learning's convolutional neural networks (CNN). Model performance was assessed using a Chinese Han population with 361 samples and a white population with 50 samples. The average accuracy of the sex estimation of the two test datasets was determined. RESULTS: For the Chinese Han population test dataset, the sex estimation accuracy was 94.6% (males: 93.9% and females: 94.7%). For the white population samples, the accuracy of sex estimation was 82.9% (males: 80.9% and females: 88.6%). The accuracy of CNN tested in the Chinese population was significantly higher than that tested in the White population (p < 0.001) CONCLUSIONS: The model based on convolutional neural networks has an accuracy similar to that of current state-of-the-art mathematical functions using manually extracted features for the Chinese Han population samples, proving to be a reliable choice for the human sex estimation.

Binary Type-II Heterojunction K7HNb6O19/g-C3N4: An Effective Photocatalyst for Hydrogen Evolution without a Co-Catalyst.

The binary type-II heterojunction photocatalyst containing g-C3N4 and polyoxoniobate (PONb, K7HNb6O19) with excellent H2 production activity was synthesized by decorating via a facile hydrothermal method for the first time. The as-fabricated Nb-CN-0.4 composite displayed a maximum hydrogen evolution rate of 359.89 µmol g-1 h-1 without a co-catalyst under the irradiation of a 300 W Xenon Lamp, which is the highest among those of the binary PONb-based photocatalytic materials reported. The photophysical and photochemistry analyses indicated that the hydrogen evolution performance could be attributed to the formation of a type-II heterojunction, which could not only accelerate the transfer of photoinduced interfacial charges, but also effectively inhibit the recombination of electrons and holes. This work could provide a useful reference to develop an inexpensive and efficient photocatalytic system based on PONb towards H2 production.

Systematic review with meta-analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases.

BACKGROUND: Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored. METHODS: Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity. RESULTS: We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12-31%, 1530 person-years, n = 9) per person-year and 25% (95% CI 12-32%, 657 person-years, n = 5) per person-year respectively. Clinical response was regained in 58% (95% CI 49-67%, 279 patients, n = 8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission. CONCLUSIONS: Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.

Twelve-week peptide-based formula therapy may be effective in inducing remission of active Crohn disease among women who are pregnant or preparing for pregnancy.

BACKGROUND: Conventional treatment for Crohn disease (CD) in pregnancy includes mesalamine, thiopurine, and anti-tumor necrosis factor (TNF)-α agents. However, women may abstain because of complications, nonresponse, or potential adverse outcomes. Peptide-based formula therapy, through oral or nasogastric feeding without other food intake, is an effective and safe therapy for active CD. Herein, We confirmed the effectiveness and safety of peptide-based formula therapy for active CD in pregnant women or those preparing for pregnancy. METHOD: Outcomes of peptide-based formula therapy to induce CD remission during pregnancy preparation and the conception period were evaluated retrospectively among 14 women. Efficacy was evaluated as the change in serum indices and inflammatory markers after 12-week treatment. Pregnancy outcomes were compared between 14 women treated with nutrition therapy and eight women using conventional CD drugs. RESULTS: After 12 weeks, 85.7% (12 of 14) of patients treated with peptide-based formula achieved remission with a significant decrease in the CD activity index (P < .001) and high-sensitivity C-reactive protein level (P = .004). There were no effects of peptide-based formula therapy on pregnancy outcomes compared with conventional CD treatment (P > .05). Among the 12 patients who achieved CD remission with exclusive peptide-based formula therapy, 10 selected to continue total or partial peptide-based formula treatment to maintain CD remission throughout pregnancy. CONCLUSION: Peptide-based formula therapy, without other food intake, may provide a safe and effective alternative to conventional CD drugs to induce disease remission among women during conception and pregnancy.

LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer.

Long non-coding RNAs (lncRNAs) regulate numerous biological processes involved in both development and carcinogenesis. Hippo-YAP/TAZ signaling, a critical pathway responsible for organ size control, is often dysregulated in a variety of cancers. However, the nature and function of YAP/TAZ-regulated lncRNAs during tumorigenesis remain largely unexplored. By profiling YAP/TAZ-regulated lncRNAs, we identified SFTA1P as a novel transcriptional target and a positive feedback regulator of YAP/TAZ signaling. Using non-small cell lung cancer (NSCLC) cell lines, we show that SFTA1P is transcriptionally activated by YAP/TAZ in a TEAD-dependent manner. Functionally, knockdown of SFTA1P in NSCLC cell lines inhibited proliferation, induced programmed cell death, and compromised their tumorigenic potential. Mechanistically, SFTA1P knockdown decreased TAZ protein abundance and consequently, the expression of YAP/TAZ transcriptional targets. We provide evidence that this phenomenon could potentially be mediated via its interaction with TAZ mRNA to regulate TAZ translation. Our results reveal SFTA1P as a positive feedback regulator of Hippo-YAP/TAZ signaling, which may serve as the molecular basis for lncRNA-based therapies against YAP/TAZ-driven cancers.

Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease.

INTRODUCTION: Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. AIMS: To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. METHODS: Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 109 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36. RESULTS: The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up. CONCLUSIONS: Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.