B-Box transcription factor BBX28 requires CONSTITUTIVE PHOTOMORPHOGENESIS1 to induce shade-avoidance response in Arabidopsis thaliana.

Shade avoidance syndrome is an important adaptive strategy. Under shade, major transcriptional rearrangements underlie the reallocation of resources to elongate vegetative structures and redefine the plant architecture to compete for photosynthesis. BBX28 is a B-box transcription factor involved in seedling de-etiolation and flowering in Arabidopsis (Arabidopsis thaliana), but its function in shade-avoidance response is completely unknown. Here, we studied the function of BBX28 using two mutant and two transgenic lines of Arabidopsis exposed to white light and simulated shade conditions. We found that BBX28 promotes hypocotyl growth under shade through the phytochrome system by perceiving the reduction of red photons but not the reduction of photosynthetically active radiation or blue photons. We demonstrated that hypocotyl growth under shade is sustained by the protein accumulation of BBX28 in the nuclei in a CONSTITUTIVE PHOTOMORPHOGENESIS1 (COP1)-dependent manner at the end of the photoperiod. BBX28 up-regulates the expression of transcription factor- and auxin-related genes, thereby promoting hypocotyl growth under prolonged shade. Overall, our results suggest the role of BBX28 in COP1 signaling to sustain the shade-avoidance response and extend the well-known participation of other members of BBX transcription factors for fine-tuning plant growth under shade.

PIF4 enhances the expression of SAUR genes to promote growth in response to nitrate.

Nitrate supply is fundamental to support shoot growth and crop performance, but the associated increase in stem height exacerbates the risks of lodging and yield losses. Despite their significance for agriculture, the mechanisms involved in the promotion of stem growth by nitrate remain poorly understood. Here, we show that the elongation of the hypocotyl of Arabidopsis thaliana, used as a model, responds rapidly and persistently to upshifts in nitrate concentration, rather than to the nitrate level itself. The response occurred even in shoots dissected from their roots and required NITRATE TRANSPORTER 1.1 (NRT1.1) in the phosphorylated state (but not NRT1.1 nitrate transport capacity) and NIN-LIKE PROTEIN 7 (NLP7). Nitrate increased PHYTOCHROME INTERACTING FACTOR 4 (PIF4) nuclear abundance by posttranscriptional mechanisms that depended on NRT1.1 and phytochrome B. In response to nitrate, PIF4 enhanced the expression of numerous SMALL AUXIN-UP RNA (SAUR) genes in the hypocotyl. The growth response to nitrate required PIF4, positive and negative regulators of its activity, including AUXIN RESPONSE FACTORs, and SAURs. PIF4 integrates cues from the soil (nitrate) and aerial (shade) environments adjusting plant stature to facilitate access to light.

EARLY FLOWERING 3 represses the nighttime growth response to sucrose in Arabidopsis.

Plant growth depends on the supply of carbohydrates produced by photosynthesis. Exogenously applied sucrose promotes the growth of the hypocotyl in Arabidopsis thaliana seedlings grown under short days. Whether this effect of sucrose is stronger under the environmental conditions where the light input for photosynthesis is limiting remains unknown. We characterised the effects of exogenous sucrose on hypocotyl growth rates under light compared to simulated shade, during different portions of the daily cycle. The strongest effects of exogenous sucrose occurred under shade and during the night; i.e., the conditions where there is reduced or no photosynthesis. Conversely, a faster hypocotyl growth rate, predicted to enhance the demand of carbohydrates, did not associate to a stronger sucrose effect. The early flowering 3 (elf3) mutation strongly enhanced the impact of sucrose on hypocotyl growth during the night of a white-light day. This effect occurred under short, but not under long days. The addition of sucrose enhanced the fluorescence intensity of ELF3 nuclear speckles. The elf3 mutant showed increased abundance of PHYTOCHROME INTERACTING FACTOR4 (PIF4), which is a transcription factor required for a full response to sucrose. Sucrose increased PIF4 protein abundance by post-transcriptional mechanisms. Under shade, elf3 showed enhanced daytime and reduced nighttime effects of sucrose. We conclude that ELF3 modifies the responsivity to sucrose according to the time of the daily cycle and the prevailing light or shade conditions.

Prevalence of HER2 overexpression and amplification in cervical cancer: A systematic review and meta-analysis.

The reported rates of HER2 positivity in cervical cancer (CC) range from 0% to 87%. The importance of HER2 as an actionable target in CC would depend on HER2 positivity prevalence. Our aim was to provide precise estimates of HER2 overexpression and amplification in CC, globally and by relevant subgroups. We conducted a PRISMA compliant meta-analytic systematic review. We searched Medline, EMBASE, Cochrane database, and grey literature for articles reporting the proportion of HER2 positivity in CC. Studies assessing HER2 status by immunohistochemistry or in situ hybridization in invasive disease were eligible. We performed descriptive analyses of all 65 included studies. Out of these, we selected 26 studies that used standardized American Society of Clinical Oncology / College of American Pathologists (ASCO/CAP) Guidelines compliant methodology. We conducted several meta-analyses of proportions to estimate the pooled prevalence of HER2 positivity and subgroup analyses using geographic region, histology, tumor stage, primary antibody brand, study size, and publication year as moderators. The estimated pooled prevalence of HER2 overexpression was 5.7% (CI 95%: 1.5% to 11.7%) I2 = 87% in ASCO/CAP compliant studies and 27.0%, (CI 95%: 19.9% to 34.8%) I2 = 96% in ASCO/CAP non-compliant ones, p < 0.001. The estimated pooled prevalence of HER2 amplification was 1.2% (CI 95%: 0.0% to 5.8%) I2 = 0% and 24.9% (CI 95%: 12.6% to 39.6%) I2 = 86%, respectively, p = 0.004. No other factor was significantly associated with HER2 positivity rates. Our results suggest that a small, but still meaningful proportion of CC is expected to be HER2-positive. High heterogeneity was the main limitation of the study. Variations in previously reported HER2 positivity rates are mainly related to methodological issues.

Phytochrome B links the environment to transcription.

Phytochrome B (phyB) senses the difference between darkness and light, the level of irradiance, the red/far-red ratio, and temperature. Thanks to these sensory capacities, phyB perceives whether plant organs are buried in the soil, exposed to full sunlight, in the presence of nearby vegetation, and/or under risk of heat stress. In some species, phyB perceives seasonal daylength cues. phyB affects the activity of several transcriptional regulators either by direct physical interaction or indirectly by physical interaction with proteins involved in the turnover of transcriptional regulators. Typically, interaction of a protein with phyB has either negative or positive effects on the interaction of the latter with a third party, this being another protein or DNA. Thus, phyB mediates the context-dependent modulation of the transcriptome underlying changes in plant morphology, physiology, and susceptibility to biotic and abiotic stress. phyB operates as a dynamic switch that improves carbon balance, prioritizing light interception and photosynthetic capacity in open places and the projection of the shoot towards light in the soil, under shade and in warm conditions.

Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

[Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma]. / Encefalopatía hiperamoniémica y hepatocarcinoma fibrolamelar.

We present the case of a young woman, 22 years old, with an aggressive form of fibrolamellar hepatocellular carcinoma. She began with the signs and symptoms of a hyperammonemic encephalopathy, an uncommon form of presentation. Fibrolamellar carcinoma is a rare liver tumor, which affects young patients without previous liver disease. Its etiology is unknown, and it has been considered as a tumor with a better prognosis than the classic hepatocellular carcinoma.

Encefalopatía hiperamoniémica y hepatocarcinoma fibrolamelar / Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma

Presentamos el caso de una mujer de 22 años con hepatocarcinoma fibrolamelar agresivo, metastásico, de rápida evolución y con una rara forma de comienzo, como una encefalopatía hiperamoniémica. El hepatocarcinoma fibrolamelar es un tumor hepático raro, que se presenta en pacientes jóvenes, sin antecedentes de hepatopatía viral o cirrótica. Su etiología es desconocida, y tradicionalmente fue considerado como de mejor pronóstico que el carcinoma hepatocelular clásico.

We present the case of a young woman, 22 years old, with an aggressive form of fibrolamellar hepatocellular carcinoma. She began with the signs and symptoms of a hyperammonemic encephalopathy, an uncommon form of presentation. Fibrolamellar carcinoma is a rare liver tumor, which affects young patients without previous liver disease. Its etiology is unknown, and it has been considered as a tumor with a better prognosis than the classic hepatocellular carcinoma.

Encefalopatía hiperamoniémica y hepatocarcinoma fibrolamelar / Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma

Presentamos el caso de una mujer de 22 años con hepatocarcinoma fibrolamelar agresivo, metastásico, de rápida evolución y con una rara forma de comienzo, como una encefalopatía hiperamoniémica. El hepatocarcinoma fibrolamelar es un tumor hepático raro, que se presenta en pacientes jóvenes, sin antecedentes de hepatopatía viral o cirrótica. Su etiología es desconocida, y tradicionalmente fue considerado como de mejor pronóstico que el carcinoma hepatocelular clásico.(AU)

We present the case of a young woman, 22 years old, with an aggressive form of fibrolamellar hepatocellular carcinoma. She began with the signs and symptoms of a hyperammonemic encephalopathy, an uncommon form of presentation. Fibrolamellar carcinoma is a rare liver tumor, which affects young patients without previous liver disease. Its etiology is unknown, and it has been considered as a tumor with a better prognosis than the classic hepatocellular carcinoma.(AU)