The American Joint Committee on Cancer (AJCC) staging system is inadequate for an accurate prognosis in nasopharyngeal carcinoma (NPC). Thus, new biomarkers are under intense investigation. Here, we ...investigated whether the density of TILs could predict prognosis in NPC. First, we used 1490 cases of nasopharyngeal carcinoma samples from two independent cohorts to evaluate the density and distribution of tumor‐infiltrating lymphocytes (TILs). Second, in one cohort, we assessed associations between TILs and clinical outcomes in 593 randomly selected samples (defined as the training set) and validated findings in the remaining 593 samples (defined as the validation set). Furthermore, we confirmed the prognostic value of TILs in a second independent cohort of 304 cases (defined as the independent set). Based on multivariable Cox regression analysis, we also established an effective prognostic nomogram including TILs to improve accuracy in predicting disease‐free survival (DFS) for patients with nondisseminated NPC. We found that high TILs in the training set were significantly associated with favorable DFS hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28–0.58, p < 0.001, overall survival (OS, HR 0.42, 95% CI 0.27–0.64, p < 0.001), distant metastasis‐free survival (DMFS, HR 0.37, 95% CI 0.23–0.58, p < 0.001) and local‐regional recurrent free survival (LRRFS, HR 0.43, 95% CI 0.25–0.73, p = 0.002). Multivariate analysis showed that TILs are an independent prognostic indicator for DFS in all cohorts. In summary, this study indicated that TILs may reflect the immunological heterogeneity of NPC and could represent a new prognostic biomarker.
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Doctors typically use tumor stage to help determine cancer prognosis, but for nasopharyngeal cancer, it is not precise enough. These authors turned to the immune system for prognostic clues. They looked at the density and distribution of tumor‐infiltrating lymphocytes (TILs) in NPC patients from China. TILs turned out to be a strong independent predictor of disease‐free survival: greater numbers of TILs, they found, meant better outcomes. Once a standardized method for evaluating TILs can be developed, this metric could be extremely valuable for predicting disease progression in NPC patients.
Plants are known for their capacity to regenerate the whole body through de novo formation of apical meristems from a mass of proliferating cells named callus. Exogenous cytokinin and auxin determine ...cell fate for the establishment of the stem cell niche, which is the vital step of shoot regeneration, but the underlying mechanisms remain unclear. Here, we show that type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs), critical components of cytokinin signaling, activate the transcription of WUSCHEL (WUS), which encodes a key regulator for maintaining stem cells. In parallel, type-B ARRs inhibit auxin accumulation by repressing the expression of YUCCAs, which encode a key enzyme for auxin biosynthesis, indirectly promoting WUS induction. Both pathways are essential for de novo regeneration of the shoot stem cell niche. In addition, the dual regulation of type-B ARRs on WUS transcription is required for the maintenance of the shoot apical meristem in planta. Thus, our results reveal a long-standing missing link between cytokinin signaling and WUS regulator, and the findings provide critical information for understanding cell fate specification.
Sepsis-induced immune dysfunction ranging from cytokines storm to immunoparalysis impacts outcomes. Monitoring immune dysfunction enables better risk stratification and mortality prediction and is ...mandatory before widely application of immunoadjuvant therapies. We aimed to develop and validate a scoring system according to patients' immune dysfunction status for 28-day mortality prediction.
A prospective observational study from a cohort of adult sepsis patients admitted to ICU between August 2013 and June 2016 at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated immune dysfunction status through measurement of baseline plasma Cytokine levels, Monocyte human leukocyte-DR expression by flow cytometry, and stimulated immune response using post LPS stimulated cytokine elevation ratio. An immune dysfunction score was created for 28-day mortality prediction and was validated.
A total of 151 patients were enrolled. Data of the first consecutive 106 septic patients comprised the training cohort, and of other 45 patients comprised the validation cohort. Among the 106 patients, 21 died and 85 were still alive on day 28 after ICU admission. (mortality rate, 19.8%). Independent predictive factors revealed via multivariate logistic regression analysis included segmented neutrophil-to-monocyte ratio, granulocyte-colony stimulating factor, interleukin-10, and monocyte human leukocyte antigen-antigen D-related levels, all of which were selected to construct the score, which predicted 28-day mortality with area under the curve of 0.853 and 0.789 in the training and validation cohorts, respectively.
The immune dysfunction scoring system developed here included plasma granulocyte-colony stimulating factor level, interleukin-10 level, serum segmented neutrophil-to-monocyte ratio, and monocyte human leukocyte antigen-antigen D-related expression appears valid and reproducible for predicting 28-day mortality.
Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system ...based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions high-risk esophageal lesions (HrELs) and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate 28 of 1556 (1.8%) was significantly higher in the experimental group than in the control group 14 of 1561 (0.9%),
= 0.029, and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups 28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively;
= 0.021. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.
Orientation selectivity (OS) is an emergent property in the primary visual cortex (V1). How OS arises from synaptic circuits remains unsolved. Here, in vivo whole-cell recordings in the mouse V1 ...revealed that simple cells received broadly tuned excitation and even more broadly tuned inhibition. Excitation and inhibition shared a similar orientation preference and temporally overlapped substantially. Neuron modeling and dynamic-clamp recording further revealed that excitatory inputs alone would result in membrane potential responses with significantly attenuated selectivity, due to a saturating input-output function of the membrane filtering. Inhibition ameliorated the attenuation of excitatory selectivity by expanding the input dynamic range and caused additional sharpening of output responses beyond unselectively suppressing responses at all orientations. This “blur-sharpening” effect allows selectivity conveyed by excitatory inputs to be better expressed, which may be a general mechanism underlying the generation of feature-selective responses in the face of strong excitatory inputs that are weakly biased.
► Mouse simple cells receive broad orientation-tuned excitation ► Input-output function of the membrane blurs orientation selectivity ► Inhibition is even more broadly tuned and temporally interplays with excitation ► Inhibition sharpens orientation selectivity by expanding excitatory dynamic range
Our objective was to assess the incidence and dose-volume predictors of radiation esophagitis (RE) in patients with breast cancer undergoing hypofractionated regional nodal irradiation.
Eligible ...patients who received intensity modulated radiation therapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy were included. The prescribed dose was 43.5 Gy in 15 fractions. RE was evaluated weekly during RT and at 1 and 2 weeks, followed by 3 and 6 months after RT, and was graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. The esophagus was contoured from the lower border level of the cricoid cartilage to the lower margin of the aortic arch. Esophageal total volume, mean dose, maximum dose, and the relative volumes (RV) and absolute volumes (AV) receiving at least 5 to 45 Gy by 5-Gy increments (RV5-RV45 and AV5-AV45) were evaluated. Univariable and multivariable logistic regression analyses were performed to determine risk factors for RE, and receiver operating characteristic curves were obtained to identify the thresholds of esophageal dosimetric parameters.
In total, 298 patients were included between May 8, 2020, and January 5, 2022 (minimum post-RT follow-up: 6 months). Grade 2 and 3 RE incidence was 40.9% (122/298) and 0.3% (1/298), respectively. No grade 4 or 5 RE was observed. Esophageal RV20-RV40 and AV35-AV40 were significantly associated with the risk of grade ≥2 RE after adjusting for tumor laterality and internal mammary nodal irradiation. RV25 and AV35 were optimum dose-volume predictors for grade ≥2 RE at thresholds 20% for RV25 (35.9% vs 60.9%; P = .04) and 0.27 mL for AV35 (31.0% vs 54.6%; P = .04).
RE is common in patients with breast cancer undergoing hypofractionated regional nodal irradiation. Maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE.
Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date. While several monogenic factors are linked to cephalic abnormalities, such as globozoospermia ...and macrozoospermia, the genetic cause of vacuolated spermatozoa remains inadequately described. Here, we analyzed whole-exome sequencing (WES) data for an individual from a consanguineous family with severely vacuolated spermatozoa. The analysis revealed a novel homozygous c.520A>G (p.Thr174Ala) variant in the archaelysin family metallopeptidase 2 (AMZ2), a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm. Multiple algorithms predicted this variant to be a damaging mutation. Consistent with an autosomal recessive mode of inheritance, this variant was inherited from heterozygous parental carriers. To investigate the potential pathogenicity of the identified variant, we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control. Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa. Our findings reveal a candidate causative gene for vacuolated spermatozoa.
Background The molecular mechanism of laryngeal squamous cell carcinoma (LSCC) is not completely clear, which leads to poor prognosis and treatment difficulties for LSCC patients. To date, no study ...has reported the exact expression level of zinc finger protein 71 (ZNF71) and its molecular mechanism in LSCC. Methods In-house immunohistochemistry (IHC) staining (33 LSCC samples and 29 non-LSCC samples) was utilized in analyzing the protein expression level of ZNF71 in LSCC. Gene chips and high-throughput sequencing data collected from multiple public resources (313 LSCC samples and 192 non-LSCC samples) were utilized in analyzing the exact mRNA expression level of ZNF71 in LSCC. Single-cell RNA sequencing (scRNA-seq) data was used to explore the expression status of ZNF71 in different LSCC subpopulations. Enrichment analysis of ZNF71, its positively and differentially co-expressed genes (PDCEGs), and its downstream target genes was employed to detect the potential molecular mechanism of ZNF71 in LSCC. Moreover, we conducted correlation analysis between ZNF71 expression and immune infiltration. Results ZNF71 was downregulated at the protein level (area under the curve AUC = 0.93, p < 0.0001) and the mRNA level (AUC = 0.71, p = 0.023) in LSCC tissues. Patients with nodal metastasis had lower protein expression level of ZNF71 than patients without nodal metastasis (p < 0.05), and male LSCC patients had lower mRNA expression level of ZNF71 than female LSCC patients (p < 0.01). ZNF71 was absent in different LSCC subpopulations, including cancer cells, plasma cells, and tumor-infiltrated immune cells, based on scRNA-seq analysis. Enrichment analysis showed that ZNF71 and its PDCEGs may influence the progression of LSCC by regulating downstream target genes of ZNF71. These downstream target genes of ZNF71 were mainly enriched in tight junctions. Moreover, downregulation of ZNF71 may influence the development and even therapy of LSCC by reducing immune infiltration. Conclusion Downregulation of ZNF71 may promote the progression of LSCC by reducing tight junctions and immune infiltration; this requires further study. Keywords: Zinc finger protein 71 (ZNF71), Laryngeal squamous cell carcinoma (LSCC), Immunohistochemistry (IHC) staining, Single-cell RNA sequencing (scRNA-seq), Molecular mechanism, Immune infiltration
Solvothermal reactions of Zn(NO3)2·6H2O with 3,6-bis(1-imidazolyl)carbazole (3,6-bmcz) and 1,4-benzenedicarboxylic acid (1,4-H2bdc), p-phenylenediacetic acid (p-H2pda), benzophenone-4,4-dicarboxylic ...acid (H2bpda) afforded three coordination polymers Zn(1,4-bdc)(3,6-bmcz)n (1), {Zn(p-pda)(3,6-bmcz)·1.5H2O}n (2) and {Zn(bpda)(3,6-bmcz)·0.25H2O}n (3). Complexes 1–3 were characterized by elemental analysis, IR, powder X-ray diffraction, and single-crystal X-ray diffraction. Complex 1 shows 3D structure with 2D nets inclined polycatenation. Complexes 2 and 3 possess an extended 3D supramolecular architecture based on their respective 2D layers through hydrogen-bonding interactions and the π···π stacking interactions. The solid state luminescent and optical properties of 1–3 at ambient temperature were also investigated. A comparative study on their photocatalytic activity toward the degradation of methylene blue in polluted water was explored.
Reactions of Zn(NO3)2 and 3,6-(1-imidazolyl)carbazole with 1,4-benzenedicarboxylic acid, p-phenylenediacetic acid or benzophenone-4,4-dicarboxylic acid afforded three coordination polymers with different topologies and photocatalytic activity.
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•Reactions of 1,4-H2bdc, p-H2pda or H2bpda with 3,6-bmcz and Zn(II) gave three CPs.•Complex 1 is a 3D entanglement.•Complex 2 or 3 is a 3D supramolecular structure based on different 2D layers.•Complex 2 exhibited good catalytic activity of methylene blue photodegradation.
A multi-glume （mg） mutant was obtained by screening the T-DNA inserted mutant pool. Anatomical observation revealed that the florets of the mutant showed elongated leafy paleas/lemmas and ...palea/lemma-like structures, just like multi-glumes. Among the 215 observed florets of the mutant, 14.27% were failed to produce pistil and stamens, 23.72% showed extra floret generated on the same rachilla, while 62.01% consisted of one to nine stamens and one to three pistils in a single floret. On the other hand, in some cases the transparent bulged vesile-like tissue could be observed at the basis of filament. The mutant showed glumaceous Iodicules, which prevented the florets from opening in natural conditions, while the absolute male and female sterility was an obvious character of the current mutant. Observation on the process of floral organ morphogenesis by a scanning electron microscopy （SEM） indicated that no phenotype difference in floret primordia was found between the wild-type and the mutant. Meanwhile, for the mutant, the beginning of stamen and pistil primordial differentiation was later than the wild type and the palea/lemma-like structure continued to differentiate after the formation of normal palea and lemma. Furthermore, in the mutant the asymmetrical division of floral primordial caused variation in the number of stamens and pistils. Therefore, the genetic analyses indicated that the mutation phenotype was a recessive trait controlled by a single gene and co-segregated with the T-DNA. Based on the phenotypic characteristics, it could be deduced that the mutant was the result of homeotic conversion from the function of the class E genes in ABCD model.
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