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Introduction: We evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC. Methods: Retrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022. Results: Thirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27–123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients.Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4–542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31–90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively. Conclusion: One-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

Introduction: Fibroadenomas are one of the most common benign breast lesions, however they have also been found on rare occasionselsewhere. These lesions usually arise frommammary-like glands (MLG) of the anogenital region which were first describedby van der Putte.Methods: This case is about a 51-year-old female who presents with symptomatic hemorrhoids and a 5 cm nodular lesion externalto the anal verge. These were removed and examined histo-pathologically.Results: Pathology revealed three hemorrhoidal specimens and the nodular lesion which was consistent with a fibroadenoma.Histologically, the nodular lesion demonstrated a benign process with ductal proliferation and estrogen receptors.Conclusions: Fibroadenomas in anatomic locations other than the breast are very uncommon. Other sites noted in prior casereports include gallbladder, prostate, arm, eyelid and anogenital region. Most of the anogenital lesions have been found on thevulva, with only six documented cases in the anal region, making this pathology exceedingly rare.

Abstract Background GRAS genes formed one of the important transcription factor gene families in plants, had been identified in several plant species. The family genes were involved in plant growth, development, and stress resistance. However, the comparative analysis of GRAS genes in Rosaceae species was insufficient. Results In this study, a total of 333 GRAS genes were identified in six Rosaceae species, including 51 in strawberry (Fragaria vesca), 78 in apple (Malus domestica), 41 in black raspberry (Rubus occidentalis), 59 in European pear (Pyrus communis), 56 in Chinese rose (Rosa chinensis), and 48 in peach (Prunus persica). Motif analysis showed the VHIID domain, SAW motif, LR I region, and PFYRE motif were considerably conserved in the six Rosaceae species. All GRAS genes were divided into 10 subgroups according to phylogenetic analysis. A total of 15 species-specific duplicated clades and 3 lineage-specific duplicated clades were identified in six Rosaceae species. Chromosomal localization presented the uneven distribution of GRAS genes in six Rosaceae species. Duplication events contributed to the expression of the GRAS genes, and Ka/Ks analysis suggested the purification selection as a major force during the evolution process in six Rosaceae species. Cis-acting elements and GO analysis revealed that most of the GRAS genes were associated with various environmental stress in six Rosaceae species. Coexpression network analysis showed the mutual regulatory relationship between GRAS and bZIP genes, suggesting the ability of the GRAS gene to regulate abiotic stress in woodland strawberry. The expression pattern elucidated the transcriptional levels of FvGRAS genes in various tissues and the drought and salt stress in woodland strawberry, which were verified by RT-qPCR analysis. Conclusions The evolution and functional analysis of GRAS genes provided insights into the further understanding of GRAS genes on the abiotic stress of Rosaceae species.

Abstract Background Drought is a common phenomenon worldwide. It is also one of the main abiotic factors that affect the growth and quality of strawberry. The dehydration-responsive element binding protein (DREB) members that belong to the APETALA2/ethylene-responsive element binding protein (AP2/EREBP) superfamily are unique transcription factors in plants that play important roles in the abiotic stress response. Results Here, a total of 119 AP2/EREBP genes were identified in Fragaria vesca, and the AP2/EREBP superfamily was divided into AP2, RAV, ERF, DREB, and soloist subfamilies, containing 18, 7, 61, 32, and one member(s), respectively. The DREB subfamily was further divided into six subgroups (A-1 to A-6) based on phylogenetic analysis. Gene structure, conserved motifs, chromosomal location, and synteny analysis were conducted to comprehensively investigate the characteristics of FvDREBs. Furthermore, transcriptome analysis revealed distinctive expression patterns among the FvDREB genes in strawberry plants exposed to drought stress. The expression of FvDREB6 of the A-2 subgroup was down-regulated in old leaves and up-regulated in young leaves in response to drought. Furthermore, qRT-PCR analysis found that FvDREB8 from the A-2 subgroup had the highest expression level under drought stress. Together, analyses with the expression pattern, phylogenetic relationship, motif, and promoter suggest that FvDREB18 may play a critical role in the regulation of FvDREB1 and FvDREB2 expression. Conclusions Our findings provide new insights into the characteristics and potential functions of FvDREBs. These FvDREB genes should be further studied as they appear to be excellent candidates for drought tolerance improvement of strawberry.

Abstract Background In plant genomes, high proportions of duplicate copies reveals that gene duplications play an important role in the evolutionary processes of plant species. A series of gene families under positive selection after recent duplication events in plant genomes indicated the evolution of duplicates driven by adaptive evolution. However, the genome-wide evolutionary features of young duplicate genes among closely related species are rarely reported. Results In this study, we conducted a systematic survey of young duplicate genes at genome-wide levels among six Rosaceae species, whose whole-genome sequencing data were successively released in recent years. A total of 35,936 gene families were detected among the six species, in which 60.25% were generated by young duplications. The 21,650 young duplicate gene families could be divided into two expansion types based on their duplication patterns, species-specific and lineage-specific expansions. Our results showed the species-specific expansions advantaging over the lineage-specific expansions. In the two types of expansions, high-frequency duplicate domains exhibited functional preference in response to environmental stresses. Conclusions The functional preference of the young duplicate genes in both the expansion types showed that they were inclined to respond to abiotic or biotic stimuli. Moreover, young duplicate genes under positive selection in both species-specific and lineage-specific expansions suggested that they were generated to adapt to the environmental factors in Rosaceae species.

Background: The most common malignancy to cause gastric outlet obstruction is primary gastric adenocarcinoma and it is followed by carcinoma of the pancreas and gallbladder. Herein, we report a case of gastric outlet obstruction secondary to metastatic lobular breast carcinoma.Case Presentation: Fifty-seven year old Caucasian female with recently diagnosed metastatic lobular breast carcinoma to skin was referred to gastroenterology for evaluation of dyspepsia and dysphagia. She has past medical history significant for acid reflux and Clostridium difficile colitis. Computed tomography of her abdomen showed diffused bowel wall thickening without evidence of bowel obstruction. Due to persistent abdominal pain, an upper endoscopy was performed. The upper endoscopy showed gastritis and gastric stenosis in the gastric antrum. These lesions were biopsied and dilated with a balloon dilator. The biopsy of the gastric antrum later showed a metastatic carcinoma of breast origin with typical tumor morphology and immune-phenotype.Conclusions: Differentiating metastatic breast carcinoma from primary gastric adenocarcinoma cannot be done using histological examination alone. Immunohistochemistry is needed to differentiate the two based on staining for estrogen and progesterone receptors. The presence of gross cystic disease fluid protein 15 is also suggestive of metastatic breast carcinoma. The stomach has a significant capacity to distend (up to 2-4 L of food) and malignant gastric outlet obstruction is often undetected clinically until a high-grade obstruction develops. Our case demonstrates valuable teaching point in terms of broadening our differentials for gastric outlet obstruction. When patients present with gastric outlet obstruction, both non-malignant and malignant causes of gastric outlet obstruction should be considered. Once adenocarcinoma has been determined to be the cause of gastric outlet obstruction, further immunohistochemistry is needed to differentiate breast carcinoma from other carcinomas. [ABSTRACT FROM AUTHOR]

Genes encoding VQ motif-containing (VQ) transcriptional regulators and WRKY transcription factors can participate separately or jointly in plant growth, development, and abiotic and biotic stress responses. In this study, 222 VQ and 645 WRKY genes were identified in six Prunus species. Based on phylogenetic tree topologies, the VQ and WRKY genes were classified into 13 and 32 clades, respectively. Therefore, at least 13 VQ gene copies and 32 WRKY gene copies were present in the genome of the common ancestor of the six Prunus species. Similar small Ks value peaks for the VQ and WRKY genes suggest that the two gene families underwent recent duplications in the six studied species. The majority of the Ka/Ks ratios were less than 1, implying that most of the VQ and WRKY genes had undergone purifying selection. Pi values were significantly higher in the VQ genes than in the WRKY genes, and the VQ genes therefore exhibited greater nucleotide diversity in the six species. Forty-one of the Prunus VQ genes were predicted to interact with 44 of the WRKY genes, and the expression levels of some predicted VQ-WRKY interacting pairs were significantly correlated. Differential expression patterns of the VQ and WRKY genes suggested that some might be involved in regulating aphid resistance in P. persica and fruit development in P. avium.

Abstract Background Plant disease resistance (R) genes are evolving rapidly and play a critical role in the innate immune system of plants. The nucleotide binding sites-leucine rich repeat (NBS-LRR) genes are one of the largest classes in plant R genes. Previous studies have focused on the NBS-LRR genes from one or several species of different genera, and the sequenced genomes of the genus Fragaria offer the opportunity to study the evolutionary processes of these R genes among the closely related species. Results In this study, 325, 155, 190, 187, and 133 NBS-LRRs were discovered from F. x ananassa, F. iinumae, F. nipponica, F. nubicola, and F. orientalis, respectively. Together with the 144 NBS-LRR genes from F. vesca, a total of 1134 NBS-LRRs containing 866 multi-genes comprised 184 gene families across the six Fragaria genomes. Extremely short branch lengths and shallow nodes were widely present in the phylogenetic tree constructed with all of the NBS-LRR genes of the six strawberry species. The identities of the orthologous genes were highly significantly greater than those of the paralogous genes, while the Ks ratios of the former were very significantly lower than those of the latter in all of the NBS-LRR gene families. In addition, the Ks and Ka/Ks values of the TIR-NBS-LRR genes (TNLs) were significantly greater than those of the non-TIR-NBS-LRR genes (non-TNLs). Furthermore, the expression patterns of the NBS-LRR genes revealed that the same gene expressed differently under different genetic backgrounds in response to pathogens. Conclusions These results, combined with the shared hotspot regions of the duplicated NBS-LRRs on the chromosomes, indicated that the lineage-specific duplication of the NBS-LRR genes occurred before the divergence of the six Fragaria species. The Ks and Ka/Ks ratios suggested that the TNLs are more rapidly evolving and driven by stronger diversifying selective pressures than the non-TNLs.

Expression of gastrointestinal biomarkers MUC1, MUC2, MUC5AC, small-intestinal mucin antigen (SIMA), villin, and CDX2 has been studied in colorectal adenocarcinoma (CRC). Little is known, however, about their expression in small-intestinal adenocarcinoma (SIA). We immunohistochemically compared 30 SIAs with 48 CRCs for the expression of these biomarkers. The results showed that all 6 proteins were variably expressed in SIA, but the frequencies of expression were significantly lower than those for CRC with the exception of MUC1. Specifically, positive staining for MUC1, MUC2, MUC5AC, SIMA, villin, and CDX2 was observed in 16 (53%), 17 (57%), 12 (40%), 15 (50%), 20 (67%), and 18 (60%) of SIAs and 25 (52%), 43 (90%), 39 (81%), 45 (94%), 47 (98%), and 47 (98%) of CRCs, respectively. In addition, SIAs more frequently exhibited a focal staining pattern for MUC2, MUC5AC, SIMA, and villin, whereas more diffuse immunoreactivity was evident in CRCs. Focal staining for MUC1 and diffuse staining for CDX2 were common for SIAs and CRCs. Furthermore, poorly differentiated SIAs tended to express MUC1 more frequently when compared with well- and moderately differentiated SIAs. These observations further support the notion that SIA is immunophenotypically distinct from CRC despite their morphologic similarity. [ABSTRACT FROM AUTHOR]

Triploid plants have larger organs, greater biomass, and strong stress resistance by preserving relatively larger amounts of photosynthetic energy. The undesirable spread of non-native invasive crop and horticultural plants into natural areas can also be reduced or eliminated by the use of triploids, because they tend to be sterile and seedless. Triploid plants have great economic value and have been useful for developing new agronomic, horticultural, and forestry plant varieties. Because of rapid advances in DNA sequencing technology, triploids may become a focus of genomic research in the future, and will create unprecedented opportunities for discovering and monitoring genomic and transcriptomic changes in unbalanced genomes. One of the new trends in genomics research is to create synthetic triploid plants as materials for the study of first genomic responses that occur immediately after triploid formation. Here, we summarize recent progress in the use of triploid plants, approaches for obtaining triploid plants, including natural selection, artificial hybridization, and endosperm regeneration, the obstacles to obtain triploids, and possible ways to overcome these difficulties. This summary of the scientific progress on triploid plants will promote understanding of how they can be generated and assist plant breeders to design new strategies for triploid breeding.

Superoxide dismutase (SOD) is an essential enzyme of the plant antioxidant system that responds to oxidative damage caused by adverse conditions. However, little is known about the SOD gene family in Vitis vinifera (Vv). In the present study, ten SOD genes, including 6 copper/zinc SODs, 2 iron SODs, and 2 manganese SODs, were identified in the grapevine genome where they were unevenly distributed on 12 chromosomes. Ten VvSOD genes were divided into three main groups based on phylogenetic analysis, subcellular localization, and the distribution of conserved protein motifs. Additionally, many cis-elements related to different stresses were found in the promoters of the 10 VvSOD genes. Syntenic analysis revealed that VvMSD1 and VvMSD2 were derived from segmental duplication, and VvCSD4 and VvCSD5 belong to a pair of tandemly duplicated genes. Gene expression analysis based on microarray data showed that the 10 VvSOD genes were expressed in all the tested tissues. Interestingly, the segmentally duplicated gene pair (VvMSD1 and VvMSD2) exhibited differential expression patterns in various organs. In contrast, the tandemly duplicated gene pair (VvCSD4 and VvCSD5) displayed similar expression patterns in the tested organs. Our results provide a basis for further functional research on the SOD gene family in grapevine.

Dehydration-responsive element binding proteins are transcription factors that play a critical role in plant response to temperature stress. Over-expression of DREB genes has been demonstrated to enhance temperature stress tolerance. A series of physiological and biochemical modifications occur in a complex and integrated way when plants respond to temperature stress, which makes it difficult to assess the mechanism underlying the DREB enhancement of stress tolerance. A meta-analysis was conducted of the effect of DREB overexpression on temperature stress tolerance and the various parameters modulated by overexpression that were statistically quantified in 75 published articles. The meta-analysis was conducted to identify the overall influence of DREB on stress-related parameters in transgenic plants, and to determine how different experimental variables affect the impact of DREB overexpression. Viewed across all the examined studies, 7 of the 8 measured plant parameters were significantly (p ≤ 0.05) modulated in DREB-transgenic plants when they were subjected to temperature stress, while 2 of the 8 parameters were significantly affected in non-stressed control plants. The measured parameters were modulated by 32% or more by various experimental variables. The modulating variables included, acclimated or non-acclimated, type of promoter, stress time and severity, source of the donor gene, and whether the donor and recipient were the same genus. These variables all had a significant effect on the observed impact of DREB overexpression. Further studies should be conducted under field conditions to better understand the role of DREB transcription factors in enhancing plant tolerance to temperature stress.

Basic leucine zipper (bZIP) genes are known to play a crucial role in response to various processes in plant as well as abiotic or biotic stress challenges. We have performed an identification and characterization of 50 bZIP genes across the woodland strawberry (Fragaria vesca) genome, which were divided into 10 clades according to the phylogenetic relationship of the strawberry bZIP proteins with those in Arabidopsis and rice. Five categories of intron patterns were observed within basic and hinge regions of the bZIP domains. Some additional conserved motifs have been found with the group specificity. Further, we predicted DNA-binding specificity of the basic and hinge regions as well as dimerization properties of leucine zipper regions, which was consistent with our phylogenetic clade and classified into 20 subfamilies. Across the different developmental stages of 15 organs and two types of fruits, the clade A bZIP members showed different tissue-specific expression patterns and the duplicated genes were differentially regulated, indicating a functional diversification coupled with the expansion of this gene family in strawberry. Under normal growth conditions, mrna11837 and mrna30280 of clade A showed very weak expression levels in organs and fruits, respectively; but higher expression was observed with different set of genes following drought and heat treatment, which may be caused by the separate response pathway between drought and heat treatments.

Asian pear (Pyrus bretschneideri) is one of the most important fruit crops in the world, and its growth and productivity are frequently affected by abiotic stresses. Calcineurin B-like interacting protein kinases (CIPKs) as caladium-sensor protein kinases interact with Ca2+-binding CBLs to extensively mediate abiotic stress responses in plants. Although the pear genome sequence has been released, little information is available about the CIPK genes in pear, especially in response to salt and osmotic stresses. In this study, we systematically identified 28 CIPK family members from the sequenced pear genome and analyzed their organization, phylogeny, gene structure, protein motif, and synteny duplication divergences. Most duplicated PbCIPKs underwent purifying selection, and their evolutionary divergences accompanied with the pear whole genome duplication. We also investigated stress -responsive expression patterns and co-expression networks of CIPK family under salt and osmotic stresses, and the distribution of stress-related cis-regulatory elements in promoter regions. Our results suggest that most PbCIPKs could play important roles in the abiotic stress responses. Some PbCIPKs, such as PbCIPK22, -19, -18, -15, -8, and -6 can serve as core regulators in response to salt and osmotic stresses based on co-expression networks of PbCIPKs. Some sets of genes that were involved in response to salt did not overlap with those in response to osmotic responses, suggesting the sub-functionalization of CIPK genes in stress responses. This study revealed some candidate genes that play roles in early responses to salt and osmotic stress for further characterization of abiotic stress responses medicated by CIPKs in pear.

The basic leucine zipper (bZIP) transcription factors are the most diverse members of dimerizing transcription factors. In the present study, 50, 116, and 47 bZIP genes were identified in Malus domestica (apple), Prunus persica (peach), and Fragaria vesca (strawberry), respectively. Species-specific duplication was the main contributor to the large number of bZIPs observed in apple. After WGD in apple genome, orthologous bZIP genes corresponding to strawberry on duplicated regions in apple genome were retained. However, in peach ancestor, these syntenic regions were quickly lost or deleted. Maybe the positive selection contributed to the expansion of clade S to adapt to the development and environment stresses. In addition, purifying selection was mainly responsible for bZIP sequence-specific DNA binding. The analysis of orthologous pairs between chromosomes indicates that these orthologs derived from one gene duplication located on one of the nine ancient chromosomes in the Rosaceae. The comparative analysis of bZIP genes in three species provides information on the evolutionary fate of bZIP genes in apple and peach after they diverged from strawberry.

Calcium-dependent protein kinases (CDPKs) are molecular switches that bind Ca(2+), ATP, and protein substrates, acting as sensor relays and responders that convert Ca(2+) signals, created by developmental processes and environmental stresses, into phosphorylation events. The precise functions of the CDPKs in grapevine (Vitis vinifera) are largely unknown. We therefore investigated the phylogenetic relationships and expression profiles of the 17 CDPK genes identified in the 12x grapevine genome sequence, resolving them into four subfamilies based on phylogenetic tree topology and gene structures. The origins of the CDPKs during grapevine evolution were characterized, involving 13 expansion events. Transcriptomic analysis using 54 tissues and developmental stages revealed three types of CDPK gene expression profiles: constitutive (housekeeping CDPKs), partitioned functions, and prevalent in pollen/stamen. We identified two duplicated CDPK genes that had evolved from housekeeping to pollen-prevalent functions and whose origin correlated with that of seed plants, suggesting neofunctionalization with an important role in pollen development and also potential value in the breeding of seedless varieties. We also found that CDPKs were involved in three abiotic stress signaling pathways and could therefore be used to investigate the crosstalk between stress responses.