PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

Minimal non-abelian nodal braiding in ideal metamaterials.

Exploring new topological phases and phenomena has become a vital topic in condensed matter physics and materials sciences. Recent studies reveal that a braided colliding nodal pair can be stabilized in a multi-gap system with [Formula: see text] or [Formula: see text] symmetry. This exemplifies non-abelian topological charges beyond the scope of conventional single-gap abelian band topology. Here, we construct ideal acoustic metamaterials to realize non-abelian braiding with the fewest band nodes. By emulating the time with a sequence of acoustic samples, we experimentally observe an elegant but nontrivial nodal braiding process, including nodes creation, braiding, collision, and repulsion (i.e., impossible to annihilate), and measure the mirror eigenvalues to elucidate the braiding consequence. The latter, at the level of wavefunctions, is of prime importance since essentially braiding physics aims to entangle multi-band wavefunctions. Furthermore, we experimentally unveil the highly intricate correlation between the multi-gap edge responses and the bulk non-abelian charges. Our findings pave the way for developing non-abelian topological physics that is still in its infancy.

Clinical, endoscopic and pathological characteristics of primary gastrointestinal T-cell and NK/T-cell lymphomas.

BACKGROUND AND AIMS: Gastrointestinal T-cell and NK/T-cell lymphomas are relatively rare and may be difficult to diagnose. Therefore, we performed a retrospective study of the clinical, endoscopic and pathological characteristics of these lymphomas, to provide additional data on this issue. METHODS: From April 2013 to April 2021, consecutive patients diagnosed with primary gastrointestinal T-cell and NK/T-cell lymphomas were retrospectively reviewed. Their medical histories, laboratory, imaging, endoscopic, and pathology results were analyzed. RESULTS: Forty-two patients were finally chosen, among whom, 24 patients had ENKTCL, 9 patients had MEITL, 2 patients had ALCL, ALK-, 1 patient had ALCL, ALK+, and 6 patients had PTCL, NOS. The median age of all the patients was 48 years old, and 73.81% (31 patients) were male. The patients' symptoms were abdominal pain, diarrhea, gastrointestinal bleeding, weight loss, fever, and others. The endoscopic results of 26 patients could be traced, and 69.23% of the patients showed multiple lesions. Ulcerative and ulceroinfiltrative lesions were common. Among the pathologic findings, necrosis, ulceration, and crypt atrophy were commonly found while epitheliotropism was relatively less common. Twelve patients (28.57%) had a history of misdiagnosis. After a median follow-up time of 26.9 months, 26 patients (66.70%) died of the disease. The median overall survival time was 8 months. CONCLUSIONS: These lymphomas had nonspecific clinical manifestations, various endoscopic features, and were likely to be misdiagnosed as other diseases. The prognosis is still poor, and more in-depth research is needed to develop more precise treatments.

Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed. METHODS: We performed whole-exome sequencing of matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. RESULTS: A total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were IGLL5 (47%), TP53 (42%), BTG2 (28%), P2RY8 (26%) and PCLO (23%). Compared to the common DLBCL, significantly less or absence of MYD88 (0%), EZH2 (0%), BCL2 (2%) or CD79B (8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the TP53 and LRP1B mutations, two established tumor suppressor genes in many human cancers. Moreover, IGLL5 and LRP1B mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL. CONCLUSIONS: Our study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL.

Integrated driver mutations profile of chinese gastrointestinal-natural killer/T-cell lymphoma.

Background: One of the most common nasal external sites in extranodal Natural Killer/T-cell lymphoma (NKTCL) is in the gastrointestinal (GI) system. Despite this, reports on gastrointestinal-Natural Killer/T-cell lymphoma (GI-NKTCL) are very few. To obtain a better understanding of this manifestation of NKTCL, we conducted a retrospective study on GI-NKTCL to analyze its clinical features, genomic changes and immune infiltration. Methods: We retrospectively collected patients diagnosed with GI-NKTCL in the Sixth Affiliated Hospital of Sun Yat-sen University from 2010 to 2020. From this cohort we obtained mutation data via whole exome sequencing. Results: Genomic analysis from 15 patients with GI-NKTCL showed that the most common driving mutations were ARID1B(14%, 2/15), ERBB3(14%, 2/15), POT1(14%, 2/15), and TP53(14%, 2/15). In addition, we found the most common gene mutation in patients with GI-NKTCL to be RETSAT(29%, 4/15) and SNRNP70(21%, 3/15), and the most common hallmark pathway mutations to be G2M checkpoint pathway (10/15, 66.7%), E2F targets (8/15, 53.3%), estrogen response late (7/15, 46.7%), estrogen response early (7/15, 46.7%), apoptosis (7/15, 46.7%) and TNFA signaling via NFKB (7/15, 46.7%). In the ICIs-Miao cohort, SNRNP7-wild-type (WT) melanoma patients had significantly prolonged overall survival (OS) time compared with SNRNP7 mutant type (MT) melanoma patients. In the TCGA-UCEC cohort, the patients with RETSAT-MT or SNRNP7-MT had significantly increased expression of immune checkpoint molecules and upregulation of inflammatory immune cells. Conclusions: In this study, we explored GI-NKTCL by means of genomic analysis, and identified the most common mutant genes (RETSAT and SNRNP70), pathway mutations (G2M checkpoint and E2F targets) in GI-NKTCL patients. Also, we explored the association between the common mutant genes and immune infiltration. Our aim is that our exploration of these genomic changes will aid in the discovery of new biomarkers and therapeutic targets for those with GI-NKTCL, and finally provide a theoretical basis for improving the treatment and prognosis of patients with GI-NKTCL.

Effects of subarachnoid extension following intracerebral hemorrhage: A systematic review and meta-analysis.

BACKGROUND: The effects of subarachnoid extension (SAHE) following intracerebral hemorrhage (ICH) have not yet been fully understood. We conducted a systematic review and meta-analysis of published literature on this topic to better understand the effects of SAHE. METHODS: PubMed, Embase, and Cochrane databases were thoroughly searched from inception to October 16, 2022 to identify studies that evaluated the association between SAHE and mortality and worse functional outcomes in primary ICH. Crude odds ratios (cOR) and adjusted odds ratios (aOR) with 95% confidence interval (CI) were calculated to compare the endpoints. RESULTS: Three studies with 3368 participants were eventually included in the analysis. In the short-term follow-up of the primary endpoint, no association was observed between SAHE and mortality (cOR: 0.51, 95% CI: 0.01-28.19; aOR: 2.31, 95% CI: 0.72-7.45). In the long-term follow-up of the primary endpoint, SAHE was associated with a significantly increased mortality of patients with primary ICH (cOR: 3.00, 95% CI: 2.27-3.98); however, only 1 study provided the values of aOR and 95% CI and showed that SAHE was not associated with increased mortality (aOR: 1.14, 95% CI: 0.71-1.83). For the secondary endpoint, the data of only 1 study on major disability (modified Rankin Scale = 3-5) were available, and the results revealed that SAHE increased the probability of major disability, but not after adjusting for baseline hematoma volume. CONCLUSION: There is insufficient evidence to demonstrate the correlation between SAHE and mortality and worse functional outcomes in primary ICH. The validation of this correlation requires further studies as the potential effect and mechanisms of SAHE remain unclear.

Amperometric immunosensor based on covalent organic frameworks and Pt/Ru/C nanoparticles for the quantification of C-reactive protein.

An ultrasensitive and nonenzymatic electrochemical sandwich-type immunoassay using covalent organic framework (COF-LZU1) material applied as a fixed matrix was developed for the determination of C-reactive protein (CRP). COFs with large specific surface area, good conductivity and stability were employed for functionalisation of the surface. Au nanoparticles were loaded on COF-LZUl to immobilise the CRP antibody (anti-CRP) on the surface of a glassy carbon electrode. Microwave method was employed for the synthesis of the Pt/Ru/C nanoparticles to imitate the protein enzyme with high catalytic activity. The as-synthesised activated carbon-supported bimetallic Pt/Ru/C nanoparticle composite was used to label secondary CRP antibody because it exhibited excellent catalytic behaviour toward hydrogen peroxide. After incubation of CRP, Pt/Ru/C-labelled anti-CRP was combined with CRP through specific antibody-antigen recognition process. The reduction current of H202 at - 0.2 V catalysing by tag Pt/Ru/C as measured by a chronoamperometric method is proportional to the concentration of CRP. Under optimal experimental conditions, employing chronoamperometry to investigate the CRP, the obtained linear range was 0.2 to 20 ng/mL with a detection limit of 0.1 ng/mL. This immunosensor provides an attractive platform for the applicability of COF-LZU1 materials and Pt/Ru/C nanoparticles in electrochemical assays. Graphical abstract An ultrasensitive and nonenzymatic electrochemical immunoassay using covalent organic frameworks (COF-LZU1) material as the fixed matrix was developed for the detection of C-reactive protein (CRP). Microwave method was employed to synthesis the bimetallic metal composites Pt/Ru/C nanoparticles, which exhibited excellent catalytic behavior toward small molecules H2O2. COFs with large specific surface area, good conductivity and stability were employed for surface functionalization. Our proposed biosensor is highly sensitive, with the detection limit of 0.1 ng/mL.

Chidamide based combination regimen for treatment of monomorphic epitheliotropic intestinal T cell lymphoma following radical operation: Two case reports.

BACKGROUND: Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) is a rare extra-nodal T-cell lymphoma that has uniformly aggressive features with a poor prognosis. No standardized treatment protocols have been established. Previous experience has demonstrated favorable outcomes with combination chemotherapy followed by autologous hematopoietic stem cell transplant. However, many patients are unable to tolerate the toxicities. Chidamide is a new histone deacetylase inhibitor that has shown preferential efficacy in mature T-cell lymphoma. CASE SUMMARY: We herein present two cases of MEITL who were both intermediate risk according to enteropathy-associated T cell lymphoma prognostic index. Case one was a 61-year-old man. He complained of upper abdominal pain and intermittent black stool for 2 mo. Imaging examination revealed that the intestinal wall was thickened. He received a partial excision of the small intestine. A chidamide-based combination regimen was given postoperatively. Eleven months later, he presented with recurrence in the bilateral lungs. He passed away 15 mo after his diagnosis. Case two was a 35-year-old woman who complained of abdominal distention for 1 mo. Positron emission tomography/computed tomography demonstrated wall thickening of the small intestine and upper sigmoid colon. Colon perforation and septic shock occurred on the fourth day of her admission. She was treated by sigmoid colostomy. Chidamide-based combination therapy was then provided. She was recurrence-free for 6 mo until lesions were found in the bilateral brain and lived for 17 mo since her diagnosis. Compared to historical data, chidamide seems to improve the prognosis of MEITL slightly. CONCLUSION: MEITL is a type of aggressive lymphoma. Chidamide is a new promising approach for the treatment of MEITL.

A prospective, crossover randomized trial of the optimal timing for leucovorin rescue after high-dose methotrexate management in adult non-Hodgkin's lymphoma patients.

This study aimed to investigate the optimal time of leucovorin rescue for HDMTX in non-Hodgkin's lymphoma (NHL) patients. Ninety-eight patients treated with HDMTX were randomly assigned to receive leucovorin at either 18 or 24 h after initiation of HDMTX infusion during the first cycle and switched to the other mode in the second cycle. All courses achieved an efficacious MTX concentration. Compared to the 18th hour group, the 24th hour group exhibited an increase in incidence of thrombocytopenia (48% versus 34.7%, p = .036) and grade III/IV neutropenia (34.7% versus 21.4%, p = .039). No bleeding occurred and the incidence of fever with grade III/IV neutropenia was low with no difference observed between the two groups. We recommend that with the HDMTX generally used most adult patients with NHL may have greater therapeutic benefit and acceptable toxicity with their LV rescue started at 24 h instead of 18 h.

A Label-Free Immunosensor for CEA Based on Pd-Ir Bimetallic Nanoparticles.

In this paper, a kind of label-free immunosensor for rapid detection of carcinoembryonic antigen (CEA) based on Pd-Ir bimetallic nanoparticles as a catalyst was prepared. CEA antibody (anti-CEA) was immobilized onto the surface of glassy carbon electrode through the adsorption effect of Pd-Ir bimetallic nanoparticles modified on the electrode using chitosan. When CEA antibody combines with CEA antigen, the formed immunocomplexs blocks the catalytic activity of Pd-Ir bimetal nanoparticles to the reduction of H2O2, leading to decrease in the current response signal. The decrease of the current response of the immunosensor has a linear relationship with the concentration of CEA ranging from 0.05 ng/mL to 50 ng/mL with a detection limit of 0.017 ng/mL at 3σ. The sensor provides a new simple method for the determination of CEA.

Metal-Organic Framework Nanomaterials as Novel Signal Probes for Electron Transfer Mediated Ultrasensitive Electrochemical Immunoassay.

A novel and simple electrochemical immunoassay for C-reactive protein was developed using metal-organic frameworks (Au-MOFs) as signal unit. In this study, we found MOFs could be used as signal probe. And this new class of signal probe differs from traditional probe. The signal of the copper ions (Cu2+) from MOFs could be directly detected without acid dissolution and preconcentration, which would greatly simplify the detection steps and reduce the detection time. Moreover, MOFs contain large amounts of Cu2+ ions, providing high electrochemical signals. Our report represents the first example of using MOFs themselves as electrochemical signal probe for biosensors. Platinum nanoparticle modified covalent organic frameworks (Pt-COFs) with high electronic conductivity was employed as the substrate, which is the first time demonstrating the use of Pt-COFs for electrochemical immunoassay. Under the optimized experimental conditions, the proposed sensing strategy provides a linear dynamic ranging from 1 to 400 ng/mL. A detection limit of 0.2 ng/mL was obtained, indicating an improved analytical performance. With these merits, this stable, simple, low-cost, sensitive and selective electrochemical immunoassay shows promise for applications in the point-of-care diagnostics of dieses and environmental monitoring.

Erosion effects of atomic oxygen on polyhedral oligomeric silsesquioxane-polyimide hybrid films in low earth orbit space environment.

A novel polyimide (PI) hybrid nanocomposite containing polyhedral oligomeric silsesquioxane (POSS) had been prepared by copolymerization of trisilanolphenyl-POSS, 4,4'-oxydianiline (ODA), and pyromellitic dianhydride (PMDA). The AO resistance of these PI/POSS hybrid films was tested in the ground-based AO simulation facility. Exposed and unexposed surfaces were characterized by SEM and X-ray photoelectron spectroscopy. SEM images showed that the surface of the 20 wt% PI/POSS became much less rough than that of the pristine polyimide. Mass measurements of the samples showed that the erosion yield of the PI/POSS (20 wt.%) hybrid film was 1.2 x 10(-25) cm3/atom, and reduced to 4% of the polyimide film. The XPS data indicated that the carbon content of the near-surface region was decreased from 60.1 to 13.2 at% after AO exposure. The oxygen and silicon concentrations in the near-surface region increased to 1.96 after AO exposure. The nanometer-sized structure of POSS, with its large surface area, had led AO-irradiated samples to form a SiO2 passivation layer, which protected the underlying polymer from further AO attack. The incorporation of POSS into the polyimide could dramatically improve the AO resistance of polyimide films in low earth orbit environment.

An open-framework rutile-type magnesium isonicotinate and its structural analogue with an anatase topology.

Two new photoluminescent magnesium-based coordination polymers, Mg(int)(2)·H(2)O (1) and Mg(nt)(2) (2), were synthesized under solvothermal conditions. Structural analyses reveal that they have different 3,6-connected frameworks with rutile- and anatase-type topologies, respectively. Compound 1 remains stable after the removal of its guest molecules and it exhibits weak ferroelectric behavior.

Treatment of poplar alkaline peroxide mechanical pulping (APMP) effluent with Aspergillus niger.

Although the moderate load (COD of 5000-10,000 mg/L) and biodegradability of the APMP pulping effluent should allow biological treatment, toxic compounds in the effluent can interfere with this type of treatment. Studies were conducted to determine if treatment of the effluent with Aspergillus niger S13 was feasible. Under the optimized conditions (3% inoculum, pH 6, shaking at 160 rpm, 60-72 h, and 30°C), this fungus was able to remove about 97% of the methyl tertiary butyl ether (MTBE) extractives, and 60%, 77% and 43% of the chemical oxygen demand, turbidity and color even without a pre-flocculation step. These results are of practical interest in China because the APMP process has become popular, and efficient and cost-effective effluent treatment technologies are in high demand.

Treatment of APMP pulping effluent based on aerobic fermentation with Aspergillus niger and post-coagulation/flocculation.

A novel two-stage biological/flocculation process was developed for treating the pulping effluent from the alkaline peroxide mechanical pulping (APMP) process. In the first biological stage, the aerobic fermentation by using Aspergillus niger can decrease the chemical oxygen demand (COD) by about 60% while producing about 7 g/l of solid biomass. In the second stage (post-coagulation/flocculation), the residual COD, turbidity and color, can be further decreased by using alum and polyacrylamide (PAM). The overall removal efficiencies of COD, color and turbidity from the APMP pulping effluent by the above two-stage biological-coagulation/flocculation process were 93%, 92% and 99%, respectively, under the conditions studied.