Small-Molecule Therapeutics Achieve Multiple Mechanism-Mediated Sensitizations of Colorectal Cancer to Immune Checkpoint Blockade via Neutrophil Micropharmacies.

Immune checkpoint blockade (ICB) therapy has been approved for colorectal cancer (CRC). However, response rates are variable and often <50%. The low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) jointly contribute to this suboptimal response rate. This study confirmed the potential of combining immunogenic cell death (ICD) inducer irinotecan (IRI) and transforming growth factor-ß (TGF-ß) inhibitor galunisertib (GAL) to improve tumor immunogenicity and remodel the immunosuppressive TME. Moreover, to ameliorate the in vivo delivery barriers associated with small molecules, neutrophil micropharmacies (NOG) were developed for the codelivery of IRI and GAL, which loaded the commercial liposome formulation of IRI (ONIVYDE, ONI) intracellularly and conjugated the pH-responsive GAL liposome (GLP) on the cell surface. This neutrophil-based formulation resulted in a >4-fold increase in the ratios of the amount of both IRI and GAL accumulated in tumors to the dosage administration, effectively achieving multiple mechanism-mediated sensitization of CRC to ICB therapy.

Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation.

Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.

Global and Chinese trends in oligonucleotide drug clinical development: A comparative analysis.

Oligonucleotide drugs are anticipated to mark the new wave of pharmaceutical innovation, succeeding the eras of small molecule drugs and monoclonal antibodies. This review assessed a decade of global and Chinese clinical advancements in this field. Since 2013, there has been a notable surge in the development of oligonucleotide drugs, although a considerable majority of these candidates are still in the nascent stages of clinical trials. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) represent two pivotal classes both on global scale and within China. Rare diseases have been the main therapeutic target for oligonucleotide drugs, with a less pronounced focus in China's pipeline relative to the global trend. Concurrently, these drugs are broadening their scope to encompass a variety of indications, potentially revolutionizing treatment approaches for chronic conditions. While China's clinical development in this sector is in its infancy compared to the global stage, technological progress and favorable policies are expected to foster a new landscape of oligonucleotide drug development in the future.

A systematic genome-wide analysis and screening of the NAC family genes related to wood formation in Cinnamomum camphora.

Many processes, such as growth, aging, and adaptation to abiotic stress, are regulated in plants by NAC transcription factors. In woody plants, NAC transcription factors acts as a primary switch that regulates secondary xylem development by activating various downstream transcription factors and modulating expression levels of genes involved in the synthesis of the secondary cell wall. Our team had previously sequenced the whole genome of the camphor tree (Cinnamomum camphora). Here, we performed a detailed analysis of the NAC gene family of C. camphora and examined its evolutionary history. The genomic sequences of 121 NAC genes of C. camphora were identified and classified into 20 subfamilies in 2 major classes based on the phylogenetic analysis and structural features. Expansion of the CcNAC gene family occurred mainly by fragment replication and was influenced by the purifying selection. By analyzing predicted interactions of the homologous AtNAC proteins, we identified five CcNACs that potentially regulate xylem development in C. camphora. RNA sequencing revealed distinct expression profiles of CcNACs in seven different plant tissues. Subcellular localization prediction revealed that 120, 3, and 2 CcNACs have biological functions in the nucleus, cytoplasm, and chloroplast, respectively. Furthermore, we verified expression patterns of five CcNACs (CcNAC012, CcNAC028, CcNAC055, CcNAC080, and CcNAC119) in various tissue types using qRT-PCR. Our results will facilitate further in-depth studies of the molecular mechanisms by which CcNAC transcription factors regulate wood formation and other processes in C. camphora.

Sunken Upper Eyelid Deformity Correction by Orbital Fat Pad Repositioning and Orbicularis Oculi Muscle Folding in Blepharoplasty.

BACKGROUND: Sunken upper eyelid deformity results in an aged and unnatural appearance and is common among Asians along with the single eyelid. The upper eyelid volume restoration is as important as the creation of a supratarsal fold for patients with sunken eyelids. In the present study, the combination of orbital fat pad repositioning and orbicularis oculi muscle flap folding was established to correct the upper eyelid depression during blepharoplasty. METHODS: A retrospective study was conducted on patients who underwent the orbital fat pad repositioning and orbicularis oculi muscle flap folding to correct the upper eyelid depression between July 2020 and October 2021. The preoperative and postoperative sunken depths were calculated and compared, and overall patient satisfaction was performed to evaluate the operation efficiency. RESULTS: There were 40 patients, including 39 females and 1 male, who underwent surgery with an average age of 25.4 years. During the mean follow-up period of 12.7 months, the sunken depth improved from 3.2 mm preoperatively to 1.5 mm postoperatively with a statistical significance. Satisfactory results were achieved without major complication. CONCLUSIONS: For patients with mild to moderate sunken upper eyelids, the combination of orbital fat pad repositioning and orbicularis oculi muscle folding has been proved efficient and consistent to restore the upper eyelid volume and helpful to build esthetic double eyelids.

Genome-Wide Characterization and Analysis of bHLH Transcription Factors Related to Anthocyanin Biosynthesis in Cinnamomum camphora ('Gantong 1').

Cinnamomum camphora is one of the most commonly used tree species in landscaping. Improving its ornamental traits, particularly bark and leaf colors, is one of the key breeding goals. The basic helix-loop-helix (bHLH) transcription factors (TFs) are crucial in controlling anthocyanin biosynthesis in many plants. However, their role in C. camphora remains largely unknown. In this study, we identified 150 bHLH TFs (CcbHLHs) using natural mutant C. camphora 'Gantong 1', which has unusual bark and leaf colors. Phylogenetic analysis revealed that 150 CcbHLHs were divided into 26 subfamilies which shared similar gene structures and conserved motifs. According to the protein homology analysis, we identified four candidate CcbHLHs that were highly conserved compared to the TT8 protein in A. thaliana. These TFs are potentially involved in anthocyanin biosynthesis in C. camphora. RNA-seq analysis revealed specific expression patterns of CcbHLHs in different tissue types. Furthermore, we verified expression patterns of seven CcbHLHs (CcbHLH001, CcbHLH015, CcbHLH017, CcbHLH022, CcbHLH101, CcbHLH118, and CcbHLH134) in various tissue types at different growth stages using qRT-PCR. This study opens a new avenue for subsequent research on anthocyanin biosynthesis regulated by CcbHLH TFs in C. camphora.

NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss.

The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in nonphlebotomized mice had only modest effects on hepatic ferritin subunit levels and nonheme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic nonheme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 messenger RNA. This NCOA4 messenger RNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1α and HIF-2α knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen- and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis.

Phagocytosis-Regulators-Based Signature to Predict the Prognosis and Chemotherapy Resistance for Breast Cancer Patients.

Phagocytosis is crucial in tumor surveillance and immune function. The association between phagocytosis and the outcomes of breast cancer patients has not been well-determined. In this study, data were downloaded from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases to investigate the role of phagocytosis in breast cancer. Data from the TCGA and GEO databases were used to investigate the prognostic role of phagocytosis in breast cancer. Then, we performed pathway enrichment analysis, copy number variation (CNV) and single-nucleotide variant (SNV) analyses, immune infiltration analysis, calculation of tumor purity, stromal score, and immune score, and consistent clustering. We also constructed a phagocytosis-regulators-based signature system to examine its association in survival and drug response. The genomic and expression differences in the phagocytosis regulators in breast cancer were systematically analyzed, explaining the widespread dysregulation of phagocytosis regulators. Using the investigated association of phagocytosis regulators with the prognosis and tumor immune environment, we constructed a prognostic model based on phagocytosis regulators. We discovered that patients with high risk scores had a poor prognosis and were negatively associated with immune functions. The model had preferential predictive performance and significantly consistent drug-resistance prediction results. Our findings suggest that the phagocytosis-factors-based scoring system can be used as a novel prognostic factor, serving as a powerful reference tool for predicting prognosis and developing methods against drug resistance.

Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice.

The mechanisms underlying thrombocytosis in patients with iron deficiency anemia remain unknown. Here, we present findings that support the hypothesis that low iron biases the commitment of megakaryocytic (Mk)-erythroid progenitors (MEPs) toward the Mk lineage in both human and mouse. In MEPs of transmembrane serine protease 6 knockout (Tmprss6-/-) mice, which exhibit iron deficiency anemia and thrombocytosis, we observed a Mk bias, decreased labile iron, and decreased proliferation relative to wild-type (WT) MEPs. Bone marrow transplantation assays suggest that systemic iron deficiency, rather than a local role for Tmprss6-/- in hematopoietic cells, contributes to the MEP lineage commitment bias observed in Tmprss6-/- mice. Nontransgenic mice with acquired iron deficiency anemia also show thrombocytosis and Mk-biased MEPs. Gene expression analysis reveals that messenger RNAs encoding genes involved in metabolic, vascular endothelial growth factor, and extracellular signal-regulated kinase (ERK) pathways are enriched in Tmprss6-/- vs WT MEPs. Corroborating our findings from the murine models of iron deficiency anemia, primary human MEPs exhibit decreased proliferation and Mk-biased commitment after knockdown of transferrin receptor 2, a putative iron sensor. Signal transduction analyses reveal that both human and murine MEP have lower levels of phospho-ERK1/2 in iron-deficient conditions compared with controls. These data are consistent with a model in which low iron in the marrow environment affects MEP metabolism, attenuates ERK signaling, slows proliferation, and biases MEPs toward Mk lineage commitment.

Cadinane- and drimane-type sesquiterpenoids produced by Paecilomyces sp. TE-540, an endophyte from Nicotiana tabacum L., are acetylcholinesterase inhibitors.

Sesquiterpenoids with diverse skeleton types are regarded as potential lead compounds in pharmacological and other applications. Herein, we report the discovery of two new cadinane-type sesquiterpenoids, paecilacadinol A (1) and B (2); two new drimane-type sesquiterpenoids, ustusol D (3) and ustusol E (4); and six known analogs (5-10) from the endophytic fungus Paecilomyces sp. TE-540, enriching the structural diversity of naturally occurring sesquiterpenoids. Their planar structures were determined on the basis of detailed interpretation of 1D and 2D NMR spectroscopy and HRESIMS data, while their stereochemical structures were established by X-ray crystallographic analyses for 1 and 3-8 and theoretical calculations for 2. Notably, compounds 1 and 2 represent novel examples of cadinane-type sesquiterpenoids with ether bonds formed by intramolecular dehydration. Compounds 5 and 6 showed moderate activities against acetylcholinesterase (AChE), with IC50 values of 43.02 ± 6.01 and 35.97 ± 2.12 µM, respectively. Docking analysis predicted that 5 bound well in the catalytic pocket of AChE via hydrophobic interactions with Trp84, Gly117, Ser122, and Tyr121 residues, while 6 was located with Asp72 and Ser122 residues.

A Systematic Review on Secondary Metabolites of Paecilomyces Species: Chemical Diversity and Biological Activity.

Fungi are well known for their ability to synthesize secondary metabolites, which have proven to be a rich resource for exploring lead compounds with medicinal and/or agricultural importance. The genera Aspergillus, Penicillium, and Talaromyces are the most widely studied fungal groups, from which a plethora of bioactive metabolites have been characterized. However, relatively little attention has been paid to the genus Paecilomyces, which has been reported to possess great potential for its application as a biocontrol agent. Meanwhile, a wide structural array of metabolites with attractive bioactivities has been reported from this genus. This review attempts to provide a comprehensive overview of Paecilomyces species, with emphasis on the chemical diversity and relevant biological activities of these metabolic products. Herein, a total of 148 compounds and 80 references are cited in this review, which is expected to be beneficial for the development of medicines and agrochemicals in the near future.

A visible-light-driven photoelectrochemical molecularly imprinted sensor based on titanium dioxide nanotube arrays loaded with silver iodide nanoparticles for the sensitive detection of benzoyl peroxide.

A novel ultrasensitive photoelectrochemical sensor for benzoyl peroxide (BPO) was constructed under visible light irradiation. A novel nanostructured material made of molecularly imprinted polymer (MIP)-modified silver iodide nanoparticle-titanium dioxide nanotube arrays (AgINPs-TiO2 NTs) was designed as a photoactive electrode (denoted as MIP@AgINPs-TiO2 NTs). AgI-sensitized TiO2 nanotube arrays were prepared by a simple dissolution-precipitation-calcination process and then employed as a matrix to graft the MIP recognition element. Such a newly designed molecularly imprinted photoelectrochemical sensor exhibits high sensitivity and selectivity for the determination of BPO. The photoelectrochemical analysis is highly linear over the BPO concentration range from 1 × 10-12 mol L-1 to 5 × 10-10 mol L-1 with a detection limit of 2.53 × 10-13 mol L-1 (S/N = 3, n = 11). The sensor designed based on a low cost and highly sensitive assay was successfully applied in the determination of BPO in spiked samples.

Fabrication of Fe3O4@Polydopamine@Bovine Serum Ablumin (BSA) and Fe3O4@Polydopamine-Ag Core-Shell Nanoparticles and Their Catalytic and Antibacterial Properties.

The submicron-sized Fe3O4 particles were synthesized by solvothermal method. Then polydopamine (PDA) was used to modify the surface of Fe3O4 particles. And then the core-shell Fe3O4@PDA@BSA (single layer and multilayer) microspheres were prepared by the layer by layer self-assembly method (SAM). In addition, Ag nanospheres were grafted onto the surface of Fe3O4@PDA particles to obtain Fe3O4@PDA-Ag core-shell nanoparticles using silver mirror reaction. The morphology and component of the obtained core-shell particles were characterized by transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). The biocompatibility of the microspheres was researched in vitro by MTT method and its magnetic properties were also evaluated. The results showed that the microsphere has excellent magnetic properties and good biological safety. Then the catalytic performance of Fe3O4@PDA-Ag microspheres for methylene blue (MB) was studied. And the antimicrobial properties of Fe3O4@PDA-Ag microspheres for Escherichia coli and Bacillus subtilis were also be discussed. The results indicated good catalytic properties and antibacterial properties.

A molecularly imprinted photoelectrochemical sensor based on the use of Bi2S3 for sensitive determination of dioctyl phthalate.

A molecularly imprinted polymer photoelectrochemical (MIP-PEC) sensor based on bismuth sulfide (Bi2S3) is described for the determination of the plasticizer dioctyl phthalate (DOP). Bi2S3 was used as the photoelectrical converter of the sensor, and visible light was utilized as the excitation source. The molecular imprinting film was prepared through the electropolymerization of monomers in the presence of DOP. Under optimal experimental conditions, the photoelectrochemical response was linearly proportional to the logarithm of the DOP concentration in the 0.5-70 pM DOP concentration range, and the detection limit was 0.1 pM. The method is highly stable and reproducible. It was applied to the determination of DOP in spiked water samples. Graphical abstract A novel molecularly imprinted photoelectrochemical sensor with high sensitivity and high selectivity based on Bi2S3 was developed for dioctyl phthalate detection. Bi2S3 was firstly used as a photoelectric converter in photoelectrochemical sensor to improve the sensitivity of the sensor. Combining photocurrent measurement with molecular imprinting technique makes the sensor highly selective.

Staged Treatment of Chest Wall Radiation-Induced Ulcer With Negative Pressure Wound Therapy and Latissimus Dorsi Myocutaneous Flap Transplantation.

Chest wall ulcer induced by postmastectomy radiation therapy (PRMT) remains challenging for plastic surgeons because of the reduced blood supply, fibrosis, and impaired cellular potential in the irradiated area. In this study, chest wall ulcer was treated with negative pressure wound therapy (NPWT) and the latissimus dorsi myocutaneous (LDM) flap reconstruction in 2 stages. A retrospective study was performed on consecutive patients with chronic radiation-induced ulcers in chest wall from June 2012 to June 2017. Surgical debridement and NPWT were performed in the first stage and the chest wall reconstructed by the LDM flap transplantation after extensive debridement in the second stage. There were 10 female patients with chest wall ulcers with a mean age of 60.3 years. The average duration of the ulcers was 21.2 months and the ulcers varied from 1 × 2 to 5 × 7 cm. Histological examination denied any recurrent breast cancer or radiation-related malignancy. Negative pressure wound therapy was applied with 100 to 125 mm Hg negative pressure during a period of 5 to 7 days in the first stage. The LDM flap varied from 11 × 15 to 15 × 20 cm. The mean follow-up was 25.9 months. All the flaps survived well with satisfactory appearance and there was no donor-site morbidity or ulcer recurrence during the follow-up period. The staged treatment of the chest wall radiation ulcer incorporated the benefits of NPWT and LDM flap. It is beneficial in increasing the blood and nutrient supply to the irradiated tissue, enhancing the debridement and promoting tissue healing, thus improving the flap survival and decreasing the ulcer recurrence.

Crystal structure of the RxLR effector PcRxLR12 from Phytophthora capsici.

RxLR genes are a prominent class of effectors in oomycetes, and almost half of these proteins contain a conserved sequence motif termed the WY domain, that may exist singly, or as divergent tandem repeats in different effectors. Here we describe the crystal structure of PcRxLR12 (63-488) from Phytophthora capsici at 3.0 Šresolution. The structure consists of five tandemly arrayed WY-domains linked to each other by short connecting helices. Superposition of the WY-2 domain on the other four domains of PcRxLR12, show that the first α-helix termed the K motif, and Loop 3 which connects α3 and α4 are the key regions of structural divergence between the WY domains. A similar pattern was observed when WY-2 was superposed on the 11 WY domains from other oomycete effectors. We also note that an added connecting helix between WY domains in some RXLR effectors, ensures that the WY domains are oriented in the same direction.

Glabellar Rejuvenation in Forehead Lift: Reversed Periosteum or Dermal Fat Graft to Cover Pedicled Glabellar Flap.

Forehead aging is characterized by wrinkles, loss of skin elasticity, brow ptosis, and soft-tissue atrophy. For patients with prominent rhytids and marked brow ptosis, forehead lift is still the most effective treatment with a persisting result. In order to eliminate the glabellar wrinkles, forehead lift usually requires the removal of the corrugator supercilii muscle and procerus, which can lead to glabellar flattening or depression. Instead of muscle removal, the corrugator supercilii muscle, procerus, and the underlying galea were dissected as a pedicled glabellar flap. Then reversed periosteum or dermal fat graft was used to cover the glabellar flap to restore the glabellar volume. From January 2005 to November 2014, a total of 164 coronal and 42 trichophytic forehead lifts were performed. Reversed periosteum was used to cover the glabellar flap in 191 patients while dermal fat graft was applied in 15 patients with a follow-up period ranging from 6 months to 10 years. There was no irregularity or depression in the glabellar region in the group of reversed periosteal flap. The take of dermal fat graft placed over the glabellar flap was minimal. Complications from surgical procedures occurred in 2.91% of the patients. There was 1 asymmetry, 4 patients with higher than desired frontal hairline for implantation of autologous follicular units, and 1 patient with scar hyperplasia. There was no hematoma or nerve injury, no permanent numbness, and no alopecia. The techniques are simple and effective to eliminate the glabellar wrinkles and maintain or restore the glabellar volume.

Orbicularis Oculi Myocutaneous Flap for Upper Cicatricial Ectropion.

The correction of cicatricial ectropion often presents a challenge to plastic surgeons because of the difficulty obtaining tissue of similar color and texture and producing minor morbidity to donor sites. The authors present the correction of upper cicatricial ectropion by rotating the orbicularis myocutaneous flap from the same lid. From April 2008 to March 2014, 8 consecutive patients with upper cicatricial ectropion underwent transfer of orbicularis oculi myocutaneous flap. The main outcome measures included the complications, recurrence, and cosmesis. All flaps were viable with partial recurrence observed in 1 severe case. Satisfactory function and cosmesis were obtained in the evaluation of the patients during the follow-up period with a 4- to 41-month range. The redundant flap which should be excised during the blepharoplasty can be used to correct upper cicatricial ectropion. Good results can be obtained because of the well-hidden incision scar and minor donor-site morbidity.

Progressive fat necrosis after breast augmentation with autologous lipotransfer: a cause of long-lasting high Fever and axillary lymph node enlargement.

UNLABELLED: Breast augmentation with autologous fat transfer has been widely practiced. However, this procedure is not exempt from complications even after technique refinement. This article aims to describe a case of long-lasting high fever, axillary node enlargement, and upper extremity dysfunction caused by liponecrosis after breast fat injection. Radiological and histological examination confirmed liponecrosis in bilateral breasts. Aspiration, drainage, and irrigation were performed along with empirical antibiotic treatment. The patient has made a full recovery from the operation. Liponecrosis, one of the complications after autologous fat grafting to the breast, may present widely different symptoms and signs. Even experienced surgeons should not underestimate it and caution should be used to maintain safety during and after the procedure. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .