Densovirus infection facilitates plant-virus transmission by an aphid.

The interactions among plant viruses, insect vectors, and host plants have been well studied; however, the roles of insect viruses in this system have largely been neglected. We investigated the effects of MpnDV infection on aphid and PVY transmission using bioassays, RNA interference (RNAi), and GC-MS methods and green peach aphid (Myzus persicae (Sulzer)), potato virus Y (PVY), and densovirus (Myzus persicae nicotianae densovirus, MpnDV) as model systems. MpnDV increased the activities of its host, promoting population dispersal and leading to significant proliferation in tobacco plants by significantly enhancing the titer of the sesquiterpene (E)-ß-farnesene (EßF) via up-regulation of expression levels of the MpFPPS1 gene. The proliferation and dispersal of MpnDV-positive individuals were faster than that of MpnDV-negative individuals in PVY-infected tobacco plants, which promoted the transmission of PVY. These results combined showed that an insect virus may facilitate the transmission of a plant virus by enhancing the locomotor activity and population proliferation of insect vectors. These findings provide novel opportunities for controlling insect vectors and plant viruses, which can be used in the development of novel management strategies.

Construction of a pathway-level model for preeclampsia based on gene expression data.

Preeclampsia (PE) is a heterogeneous disease that seriously affects the health of mothers and fetuses. Lack of detection assays, its diagnosis and intervention are often delayed when the clinical symptoms are atypical. Using personalized pathway-based analysis and machine learning algorithms, we built a PE diagnosis model consisting of nine core pathways using multiple cohorts from the Gene Expression Omnibus database. The model showed an area under the receiver operating characteristic (AUROC) curve of 0.959 with the data from the placental tissue samples in the development cohort. In the two validation cohorts, the AUROCs were 0.898 and 0.876, respectively. The model also performed well with the maternal plasma data in another validation cohort (AUROC: 0.815). Moreover, we identified tyrosine-protein kinase Lck (LCK) as the hub gene in this model and found that LCK and pLCK proteins were downregulated in placentas from PE patients. The pathway-level model for PE can provide a novel direction to develop molecular diagnostic assay and investigate potential mechanisms of PE in future studies.

ChIP-seq and RNA-seq Reveal the Involvement of Histone Lactylation Modification in Gestational Diabetes Mellitus.

Lactylation is a novel post-translational modification of proteins. Although the histone lactylation modification has been reported to be involved in glucose metabolism, its role and molecular pathways in gestational diabetes mellitus (GDM) are still unclear. This study aims to elucidate the histone lactylation modification landscapes of GDM patients and explore lactylation-modification-related genes involved in GDM. We employed a combination of RNA-seq analysis and chromatin immunoprecipitation sequencing (ChIP-seq) analysis to identify upregulated differentially expressed genes (DEGs) with hyperhistone lactylation modification in GDM. We demonstrated that the levels of lactate and histone lactylation were significantly elevated in GDM patients. DEGs were involved in diabetes-related pathways, such as the PI3K-Akt signaling pathway, Jak-STAT signaling pathway, and mTOR signaling pathway. ChIP-seq analysis indicated that histone lactylation modification in the promoter regions of the GDM group was significantly changed. By integrating the results of RNA-seq and ChIP-seq analysis, we found that CACNA2D1 is a key gene for histone lactylation modification and is involved in the progression of GDM by promoting cell vitality and proliferation. In conclusion, we identified the key gene CACNA2D1, which upregulated and exhibited hypermodification of histone lactylation in GDM. These findings establish a theoretical groundwork for the targeted therapy of GDM.

Highly stereoselective α-glycosylation with GalN3 donors enabled collective synthesis of mucin-related tumor associated carbohydrate antigens.

Mucin-related tumor-associated carbohydrate antigens (TACAs) are important and interesting targets for cancer vaccine therapy. However, efficient access to a library of mucin-related TACAs remains a challenging task. One of the key issues is the challenging construction of α-GalNAc linkages. Here, we report highly stereoselective α-glycosylation with GalN3N-phenyl trifluoroacetimidate donors, which features excellent yields, outstanding stereoselectivities, broad substrate scope and mild reaction conditions. This method is successfully applied to highly stereoselective synthesis of GalN3-α-O-Ser, which served as the common intermediate for collective synthesis of a wide range of TACAs including TN antigen, STN antigen, 2,6 STF antigen, 2,3 STF antigen, glycophorin and cores 1-8 mucin-type O-glycans. In particular, the rationale for this highly stereoselective α-glycosylation is provided for the first time using DFT calculations and mechanistic studies, highlighting the crucial roles of reagent combinations (TMSI and Ph3PO) and the H-bonding directing effect of the N3 group.

Ligand-Dominated Activation of CO2 and CS2 by the Putative Nickel Phosphiniminato Intermediates.

Room-temperature photoactivation of the first- and second-generation PN3P-pincer nickel azido complexes 1a and 1b in the presence of CO2 or CS2 afforded N-bound carbamates, dithiocarbamates, and isothiocyanates, providing insights into CO2 and CS2 activation and demonstrating how a seemingly small difference in the ligand structure significantly influences the reactivity. Theoretical calculations disclosed that the charge of the phosphorus atom plays a critical role in determining the nitrogen atom transfer to form a plausible nickel phosphiniminato intermediate.

Gut microbiome as a treatment in colorectal cancer.

BACKGROUND: The gut microbiome plays a role in the development and progression of colorectal cancer (CRC). AIM AND OBJECTIVE: This review focuses on whether the gut microbiome is involved in the development and regulation of the host immune system. METHODS: The gut microbiome can influence the production and activity of immune cells and molecules that help to maintain the integrity of the intestinal barrier and prevent inflammation. Gut microbiota modulates the anti-cancer immune response. The gut microbiota can influence the function of immune cells, like T cells, that recognize and eliminate cancer cells. Gut microbiota can affect various aspects of cancer progression and the efficacy of various anti-cancer treatments. RESULTS: Gut microbiota provide promise as a potential biomarker to identify the effect of immunotherapy and as a target for modulation to improve the efficacy of immunotherapy in CRC treatment. CONCLUSION: The potential synergistic effect between the gut microbiome and anti-cancer treatment modalities provides an interest in developing strategies to modulate the gut microbiome to improve the efficacy of anti-cancer treatment.

This review focuses on the gut microbiome in the development and regulation of the host immune system. Gut microbiota provides potential biomarkers to identify the effect of immunotherapy and as a target for modulation of immunotherapy in the treatment of CRC. This provides potential synergistic effects between the gut microbiome and anti-cancer treatment modalities.

Highly Stereoselective Synthesis of Branched Fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with Potent Antiosteoporosis Activities.

The branched fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with potent antiosteoporosis activities have been synthesized for the first time. The synthetic approach highlights the following features: (1) 6-O-picoloyl-directed ß-d-fructofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy for the highly stereoselective constructions of ß-(2 → 6)-d-fructofuranosidic linkages and ß-(2 → 1)-d-fructofuranosidic linkages in the internal positions under the reaction conditions (DBDMH, -20 °C, CH2Cl2) and (2) the reaction conditions (DBDMH, -78 °C to -35 °C, toluene) for highly stereoselective formations of ß-(2 → 1)-d-fructofuranosidic linkages in the terminal positions.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

Dodecahedral hollow multi-shelled Co3O4/Ag:ZnIn2S4 photocatalyst for enhancing solar energy utilization efficiency.

Employing semiconductor photocatalysts featuring a hollow multi-shelled (HoMs) structure to establish a heterojunction is an effective approach to addressing the issues of low light energy utilization and severe recombination of photogenerated charge carriers. To take advantage of these key factors in semiconductor photocatalysis, here, a dodecahedral HoMs Co3O4/Ag:ZnIn2S4 photocatalyst (denoted as Co3O4/AZIS) was firstly synthesized by coupling Ag+-doped ZnIn2S4 (AZIS) nanosheets with dodecahedral HoMs Co3O4. The unique HoMs structure of the photocatalyst can not only effectively promote the separation and transfer of photo-induced charge, but also improve the utilization rate of visible light, exposing rich active sites for the photocatalytic redox reaction. The photocatalytic experiment results showed that the Co3O4/90.0 wt% AZIS photocatalyst has a high hydrogen (H2) production rate (695.0 µmol h-1 g-1) and high methyl orange (MO) degradation rate (0.4243 min-1). This work provides a feasible strategy for the development of HoMs heterojunction photocatalysts with enhanced H2 production and degradation properties of organic dyes.

One-Pot Assembly of Mannose-Capped Lipoarabinomannan Motifs up to 101-Mer from the Mycobacterium tuberculosis Cell Wall.

Lipoarabinomannan (LAM) from the Mycobacterium tuberculosis cell envelope represents important targets for the development of new therapeutic agents against tuberculosis, which is a deadly disease that has plagued mankind for a long time. However, the accessibility of long, branched, and complex lipoarabinomannan over 100-mer remains a long-standing challenge. Herein, we report the modular synthesis of mannose-capped lipoarabinomannan 101-mer from the M. tuberculosis cell wall using a one-pot assembly strategy on the basis of glycosyl ortho-(1-phenylvinyl)benzoates (PVB), which not only accelerates the modular synthesis but also precludes the potential problems associated with one-pot glycosylation with thioglycosides. Shorter sequences including 18-mer, 19-mer, and 27-mer are also synthesized for in-depth structure-activity relationship biological studies. Current synthetic routes also highlight the following features: (1) streamlined synthesis of various linear and branched glycans using one-pot orthogonal glycosylation on the combination of glycosyl N-phenyltrifluoroacetimidates, glycosyl ortho-alkynylbenzoates, and glycosyl PVB; (2) highly stereoselective construction of 10 1,2-cis-arabinofuranosyl linkages using 5-O-(2-quinolinecarbonyl)-directing 1,2-cis-arabinofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy; and (3) convergent [(18 + 19) × 2 + 27] one-pot synthesis of the 101-mer LAM polysaccharide. The present work demonstrates that this orthogonal one-pot glycosylation strategy can highly streamline the chemical synthesis of long, branched, and complex polysaccharides.

Association of a novel frameshift variant and a known deleterious variant in MMR genes with Lynch syndrome in Chinese families.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This condition is characterized by germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. In this study, we analyzed the molecular defects and clinical manifestations of two families affected with CRC and proposed appropriate individual preventive strategies for all carriers of the variant. METHODS: We recruited two families diagnosed with CRC and combined their family history and immunohistochemical results to analyze the variants of probands and those of other family members by using whole exome sequencing. Subsequently, gene variants in each family were screened by comparing them with the variants available in the public database. Sanger sequencing was performed to verify the variant sites. An online platform ( https://www.uniprot.org ) was used to analyze the functional domains of mutant proteins. RESULTS: A novel frameshift variant (NM_001281492, c.1129_1130del, p.R377fs) in MSH6 and a known deleterious variant (NM_000249.4:c.1731G > A, p.S577S) in MLH1 were identified in the two families with CRC. Using bioinformatics tools, we noted that the frameshift variant reduced the number of amino acids in the MSH6 protein from 1230 to 383, thereby leading to no MSH6 protein expression. The silent variant caused splicing defects and was strongly associated with LS. 5-Fluorouracil-based adjuvant chemotherapy is not recommended for patients with LS. CONCLUSIONS: The novel frameshift variant (MSH6, c.1129_1130del, p.R377fs) is likely pathogenic to LS, and the variant (MLH1, c.1731G > A, p.S577S) has been further confirmed to be pathogenic to LS. Our findings underscore the significance of genetic testing for LS and recommend that genetic consultation and regular follow-ups be conducted to guide individualized treatment for cancer-afflicted families, especially those with a deficiency in MMR expression.

A missense GDF5 variant causes brachydactyly type A1 and multiple-synostoses syndrome 2.

Objective: This study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple-synostoses syndrome 2 (SYNS2). Methods: A Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole-exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I-TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins. Results: The family was found to have an autosomal-dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue. Conclusions: A single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist- and receptor-binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid / El fenofibrato normaliza la fosfatasa alcalina y mejora los resultados a largo plazo en pacientes con colangitis biliar primaria avanzada refractaria al ácido ursodesoxicólico

Background: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. Aims: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. Methods: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan–Meier plots with inverse probability of treatment weighting (IPTW). Results: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07–0.75, P=0.015; and HR: 11.66, 95% CI: 5.02–27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. (AU)

Antecedentes: Aunque los pacientes con enfermedad hepática avanzada se han incluido en los estudios que evalúan los fibratos para el tratamiento de la colangitis biliar primaria, la frecuencia de las respuestas bioquímicas y los efectos adversos para este grupo de pacientes no se informó por separado y de forma exhaustiva. Objetivos: Evaluar la eficacia y la seguridad del tratamiento adicional con fenofibrato en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico. Métodos: Se analizaron los pacientes de forma retrospectiva para determinar los efectos terapéuticos clínicos del ácido ursodesoxicólico con terapia adicional de fenofibrato frente a la monoterapia continuada con ácido ursodesoxicólico. La supervivencia sin trasplante de hígado y las tasas de normalización de la fosfatasa alcalina se estimaron mediante análisis de regresión de Cox y gráficos de Kaplan-Meier con ponderación de la probabilidad inversa del tratamiento. Resultados: Se incluyeron un total de 118 pacientes: 54 recibieron ácido ursodesoxicólico solo y 64 recibieron ácido ursodesoxicólico en combinación con el tratamiento con fenofibrato. En los grupos de fenofibrato y ácido ursodesoxicólico, 37 y 11% de los pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico, respectivamente, lograron la normalización de la fosfatasa alcalina (p=0,001). El tratamiento adicional con fenofibrato mejoró tanto la supervivencia libre de trasplante de hígado como la tasa de normalización de la fosfatasa alcalina tras la ponderación de la probabilidad inversa del tratamiento (cociente de riesgos: 0,23, intervalo de confianza del 95% [IC 95%]: 0,07-0,75, p=0,015; y cociente de riesgos: 11,66, IC 95%: 5,02–27,06, p=0,001, respectivamente). (AU)

Modular and Stereoselective One-Pot Total Synthesis of Icosasaccharide Motif from Cordyceps sinensis EPS-1A Glycan.

The first stereoselective one-pot synthesis of the icosasaccharide motif of EPS-1A glycan from Cordyceps sinensis has been achieved. The synthetic approach highlights the following features: (1) merging reagent modulation and remote anchimeric assistance α-glycosylation strategy for the highly stereoselective formation of five and ten continuous 1,2-cis glucosidic bonds; (2) the strategic employment of glycosyl N-phenyltrifluoroacetimidates and glycosyl o-(1-phenylvinyl)benzoates as the matched pair for efficient orthogonal one-pot synthesis; and (3) [11 + 8 + 1] orthogonal one-pot glycosylation for the efficient assembly of the target icosasaccharide.

Collaborative Camouflaged Object Detection: A Large-Scale Dataset and Benchmark.

In this article, we provide a comprehensive study of a new task called collaborative camouflaged object detection (CoCOD), which aims to simultaneously detect camouflaged objects with the same properties from a group of relevant images. To this end, we meticulously construct the first large-scale dataset, termed CoCOD8K, which consists of 8528 high-quality and elaborately selected images with object mask annotations, covering five superclasses and 70 subclasses. The dataset spans a wide range of natural and artificial camouflage scenes with diverse object appearances and backgrounds, making it a very challenging dataset for CoCOD. Besides, we propose the first baseline model for CoCOD, named bilateral-branch network (BBNet), which explores and aggregates co-camouflaged cues within a single image and between images within a group, respectively, for accurate camouflaged object detection (COD) in given images. This is implemented by an interimage collaborative feature exploration (CFE) module, an intraimage object feature search (OFS) module, and a local-global refinement (LGR) module. We benchmark 18 state-of-the-art (SOTA) models, including 12 COD algorithms and six CoSOD algorithms, on the proposed CoCOD8K dataset under five widely used evaluation metrics. Extensive experiments demonstrate the effectiveness of the proposed method and the significantly superior performance compared to other competitors. We hope that our proposed dataset and model will boost growth in the COD community. The dataset, model, and results will be available at: https://github.com/zc199823/BBNet-CoCOD.

Corrigendum: A heterozygous mutation in NOTCH3 in a Chinese family with CADASIL.

[This corrects the article DOI: 10.3389/fgene.2022.943117.].

Recent Advances in Chemical Synthesis of Structural Domains of Lipopolysaccharides from the Commensal Gut-Associated Microbiota.

Lipopolysaccharides from the commensal gut-associated microbiota are interesting biomolecules for the treatment of various inflammatory diseases. Different from pathogenic lipopolysaccharides, commensal lipopolysaccharides have distinct chemical structures and mediate beneficial homeostasis with the immune system of the host. However, the accessibility issues of homogenous and pure commensal lipopolysaccharides hampered the in-depth studies of their functions. In this concept article, we highlight the recent synthesis of lipopolysaccharides from gut-associated lymphoid-tissue-resident Alcaligenes faecalis and Bacteroides vulgatus, which hopes to inspire the more efforts devoting to these fantastic biomolecules.

Recent chemical synthesis of plant polysaccharides.

Here, chemical syntheses of long, branched and complex glycans over 10-mer from plants are summarized, which highlights amylopectin 20-mer from starch, 17-mer from carthamus tinctorius, α-glucan 30-mer from Longan, 19-mer from psidium guajava and 11-mer from dendrobium huoshanense. The glycans assembly strategies, protecting groups utilization and glycosylation methods discussed here will inspire the efficient synthesis of diverse complex glycans with many 1,2-cis glycosidic linkages.

Identification of a novel CNV at the APC gene in a Chinese family with familial adenomatous polyposis.

Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed. Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676-112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product. Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.