Radioactive iodine therapy improves overall survival outcome in oncocytic carcinoma of the thyroid by reducing death risks from noncancer causes: A competing risk analysis of 4641 patients.

BACKGROUND: Oncocytic carcinoma of the thyroid (OCA) is an independent type of thyroid cancer. Radioactive iodine (RAI) therapy was frequently administered to OCA patients, but its contribution to improving survival is indefinite. METHODS: 4641 OCA patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazard regression and competing risk analysis were applied. RESULTS: Tumor size, SEER stage, primary surgery, and neck dissection were prognostic factors for cancer-specific survival. The results of competing risk analysis demonstrated that age over 55 years dramatically increased non-OCA death risks. Treatments that improve non-OCA survival (including total thyroidectomy, RAI therapy, and systemic therapy) should be recommended in OCA patients older than 55 years of age. Neck lymphadenectomy should not be recommended for OCA, since the metastatic lymph node ratio was low (about 3%). CONCLUSIONS: RAI therapy can improve survival in OCA by reducing noncancer death risks.

Comparative study between poorly differentiated thyroid cancer and anaplastic thyroid cancer: real-world pathological distribution, death attribution, and prognostic factor estimation.

Background: The clinic-pathological boundary between poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) is unclear due to a wide spectrum of histopathological features and the rarity of the disease. In addition to that, with the highest mortality rate and non-standard treatment modality, the PDTC/ATC population has not been subjected to comprehensive description and comparison with the extent of histological characteristics, therapeutic response, prognostic factors, and death attribution analysis. Method: A total of 4,947 PDTC/ATC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival curve estimation and Cox proportional hazard regression were applied. Results: Overall, the 5- and 10-year DSS for PDTC were 71.9% and 68.0%, respectively, whereas the 5- and 10-year OS are 59.3% and 51.2%, respectively. The median survival time for ATC patients was 3 months with 1-year OS being 26.9% and 1-year DSS being 31.2%. During the follow-up period, 68.1% of the PDTC/ATC cohort were dead, 51.6% of which were attributed to thyroid malignancies and 16.5% to non-thyroid causes. The top three common non-thyroid causes of death were miscellaneous cancers, lower respiratory system disease, and heart disease. The histological feature of papillary thyroid cancer (PTC) was the leading pathological category for PDTC patients (51.7%), whereas 76.7% of ATC patients' pathological feature was characterized as unidentifiable. Sarcoma histological characteristics found in ATC cases suffer the highest overall mortality (vs. PTC, HR = 2.61, 95% CI 1.68-4.06, P < 0.001). Older age unidentifiable histology feature, more advanced AJCC N1b, AJCC M1, and SEER stage, tumor size larger than 5 cm, and more invasive tumor extension were independent bad outcome predictors. Conclusion: The populational analysis of the PDTC/ATC cohort has provided reliable support for better understanding of the difference between PDTC and ATC cases and the guidance of clinical practice and further studies.

High-Resolution Profiling of Human Vocal Fold Cellular Landscapes With Single-Nuclei RNA Sequencing.

INTRODUCTION: The function of the vocal folds (VFs) is determined by the phenotype, abundance, and distribution of differentiated cells within specific microenvironments. Identifying this histologic framework is crucial in understanding laryngeal disease. A paucity of studies investigating VF cellular heterogeneity has been undertaken. Here, we examined the cellular landscape of human VFs by utilizing single-nuclei RNA-sequencing. METHODS: Normal true VF tissue was excised from five patients undergoing pitch elevation surgery. Tissue was snap frozen in liquid nitrogen and subjected to cellular digestion and nuclear extraction. Nuclei were processed for single-nucleus sequencing using the 10X Genomics Chromium platform. Sequencing reads were assembled using cellranger and analyzed with the scanpy package in python. RESULTS: RNA sequencing revealed 18 global cell clusters. While many were of epithelial origin, expected cell types, such as fibroblasts, immune cells, muscle cells, and endothelial cells were present. Subcluster analysis defined unique epithelial, immune, and fibroblast subpopulations. CONCLUSION: This study evaluated the cellular heterogeneity of normal human VFs by utilizing single-nuclei RNA-sequencing. With further confirmation through additional spatial sequencing and microscopic imaging, a novel cellular map of the VFs may provide insight into new cellular targets for VF disease. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids.

To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease. Highlights: BMP signaling fine-tunes the co-differentiation of mesoderm and endoderm.The cellular composition in multilineage organoids resembles that of human fetal organs.Mesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics.Multilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders.

Health Care Costs Following Anterior Cervical Discectomy and Fusion or Cervical Disc Arthroplasty.

STUDY DESIGN: Observational cohort study. OBJECTIVE: To describe the postoperative costs associated with both anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) in the two-year period following surgery. SUMMARY OF BACKGROUND DATA: CDA has become an increasingly common alternative to ACDF for the treatment of cervical disc disorders. Although a number of studies have compared clinical outcomes between both procedures, much less is known about the postoperative economic burden of each procedure. MATERIALS AND METHODS: By analyzing a commercial insurance claims database (Marketscan, Merative), patients who underwent one-level or two-level ACDF and CDA procedures between January 1, 2017 and December 31, 2017 were identified and included in the study. The primary outcome was the cost of payments for postoperative management in the two-year period following ACDF or CDA. Identified postoperative interventions included in the study were: (i) physical therapy, (ii) pain medication, (iii) injections, (iv) psychological treatment, and (iv) subsequent spine surgeries. RESULTS: Totally, 2304 patients (age: 49.0±9.4 yr; male, 50.1%) were included in the study. In all, 1723 (74.8%) patients underwent ACDF, while 581 (25.2%) underwent CDA. The cost of surgery was similar between both groups (ACDF: $26,819±23,449; CDA: $25,954±20,620; P =0.429). Thirty-day, 90-day, and two-year global costs were all lower for patients who underwent CDA compared with ACDF ($31,024 vs. $34,411, $33,064 vs. $37,517, and $55,723 vs. $68,113, respectively). CONCLUSION: Lower two-year health care costs were found for patients undergoing CDA compared with ACDF. Further work is necessary to determine the drivers of these findings and the associated longer-term outcomes.

Anterior Cervical Discectomy and Fusion With Structural Allograft is Associated With Lower Postoperative Health Care Utilization and Reoperations Compared With Cage Implants.

BACKGROUND AND OBJECTIVES: Implants represent a large component of surgical cost, with several available options for anterior cervical discectomy and fusion (ACDF). Rising ACDF volume highlights the need for accurate cost characterization among implant configurations to inform efficient utilization. METHODS: A cohort study of patients who underwent 1-level or 2-level ACDF in 2017 was conducted using the MarketScan national insurance databases, which contain deidentified clinical and financial data. Implant configurations included plate with cage, standalone cage, and plate with structural allograft. Patients who switched insurance providers within 2 years after surgery or underwent concurrent posterior cervical surgery, cervical disk arthroplasty, or cervical corpectomy were excluded. A combined plate/cage and standalone cage group was compared with the allograft group followed by the comparison of the plate/cage and standalone cage groups. In total, 30-day, 90-day, and 2-year aggregate costs; component costs of physical therapy, injections, medications, psychological treatment, and subsequent spine surgery; and reoperation rates were evaluated. RESULTS: Of 1723 patients identified, 360 (20.9%) underwent surgery with plate/cage, 184 (10.7%) with standalone cage, and 1179 (68.4%) with allograft. Aggregate costs were lower in the allograft group compared with the combined cage group at 90 days ($36 428 vs $39 875, P = .04) and 2 years ($64 951 vs $74 965, P = .005) postoperatively. There were no significant differences in aggregate costs between the plate/cage and standalone cage groups. The 2-year reoperation rate was higher in the combined cage compared with the allograft group (23.9% vs 10.9%, P < .001) and was also higher in the standalone cage compared with the plate/cage group (32.0% vs 19.7%, P = .002). CONCLUSION: Compared with alternative ACDF constructs, allograft is associated with lower postoperative costs and reoperation rates. Although costs are similar, reoperation rates are lower with plate/cage constructs compared with those of standalone cages. Surgeons should consider these financial and clinical differences when selecting implant configurations.

Structure-based development of a canine TNF-α-specific antibody using adalimumab as a template.

The canine anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody is a potential therapeutic option for treating canine arthritis. The current treatments for arthritis in dogs have limitations due to side effects, emphasizing the need for safer and more effective therapies. The crystal structure of canine TNF-α (cTNF-α) was successfully determined at a resolution of 1.85 Å, and the protein was shown to assemble as a trimer, with high similarity to the functional quaternary structure of human TNF-α (hTNF-α). Adalimumab (Humira), a known TNF-α inhibitor, effectively targets and neutralizes TNF-α to reduce inflammation and has been used to manage autoimmune conditions such as rheumatoid arthritis. By comparing the structure of cTNF-α with the complex structure of hTNF-α and adalimumab-Fab, the epitope of adalimumab on cTNF-α was identified. The significant structural similarities of epitopes in cTNF-α and hTNF-α indicate the potential of using adalimumab to target cTNF-α. Therefore, a canine/human chimeric antibody, Humivet-R1, was created by grafting the variable domain of adalimumab onto a canine antibody framework derived from ranevetmab. Humivet-R1 exhibits potent neutralizing ability (IC50 = 0.05 nM) and high binding affinity (EC50 = 0.416 nM) to cTNF-α, comparable to that of adalimumab for both hTNF-α and cTNF-α. These results strongly suggest that Humivet-R1 has the potential to provide effective treatment for canine arthritis with reduced side effects. Here, we propose a structure-guided antibody design for the use of a chimeric antibody to treat canine inflammatory disease. Our successful development strategy can speed up therapeutic antibody discovery for animals and has the potential to revolutionize veterinary medicine.

Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern.

Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

Time to surgery: A health equity metric in breast cancer patients.

BACKGROUND: We evaluated whether time to surgery by race can be a health equity metric of surgical access. METHODS: An observational analysis was performed using the National Cancer Database from 2010 to 2019. Inclusion criteria were women with stage I-III breast cancer. We excluded women with multiple cancers and whose diagnosis was made at a different hospital. The primary outcome variable was surgery within 90 days of diagnosis. RESULTS: A total of 886,840 patients were analyzed, with 76.8% White and 11.7% Black patients. 11.9% of patients experienced delayed surgery, which was significantly more common in Black patients than White patients. On adjusted analysis, Black patients were still significantly less likely to receive surgery within 90 days when compared to White patients (OR 0.61, 95% CI 0.58-0.63). CONCLUSION: The delay in surgery experienced by Black patients highlights the contribution of system factors in cancer inequity and should be a focus for targeted interventions.

Breathing-induced forces influence lung cell fate.

Respiration exerts a mechanical strain on the lungs, which has an unclear effect on epithelial cell fate. Now in Cell, Shiraishi et al.1 reveal the crucial role of mechanotransduction in maintaining lung epithelial cell fate, representing a significant milestone in understanding how mechanical factors regulate differentiation.

Early vs Delayed Transurethral Surgery in Acute Urinary Retention: Does Timing Make a Difference?

PURPOSE: Our goal was to compare outcomes of early vs delayed transurethral surgery for benign prostatic hyperplasia after an episode of acute urinary retention compared to men without preoperative acute retention. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from the New York Statewide Planning and Research Cooperative System from 2002-2016. We identified men ≥40 years old who underwent primary ambulatory transurethral resection or photoselective vaporization of the prostate, assessing surgical failure as time to reoperation or recatheterization. We categorized presurgical acute urinary retention by number of episodes: none (reference), 1, or ≥2 precatheterizations, and time from first retention episode to surgery: none (reference), 0-6 months, and >6 months. We used Fine-Gray competing-risk models to predict surgical failure at 10 years, with presurgical acute retention as the primary predictor, adjusted for age, race, insurance, Charlson Comorbidity Index score, preoperative urinary infection, and procedure type, with death as the competing risk. RESULTS: Among 17,474 patients undergoing transurethral surgery, 10% had preoperative acute retention with a median time to surgery of 2.4 months (IQR: 1-18). Among men with preoperative retention, 37% had ≥6 months of delay to surgery. The 10-year cumulative treatment failure rate was 17.2% among catheter naïve men vs 34.0% with ≥2 precatheterizations and 32.9% with ≥6 months delay to surgery. Delays from catheterization to surgery were associated with higher rates of treatment failure (<6 months SHR 1.49, P < .001; ≥6 months SHR 2.11, P < .001) vs catheter naïve men. CONCLUSIONS: Preoperative acute urinary retention and delay to surgery once catheterized are associated with poorer long-term postoperative outcomes after surgery for benign prostatic hyperplasia.

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling.

Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

The Cost of Stiffness After Total Knee Arthroplasty.

BACKGROUND: Stiffness after primary total knee arthroplasty (TKA) is debilitating and poorly understood. A heterogenous approach to the treatment is often utilized, including both nonoperative and operative treatment modalities. The purpose of this study was to examine the prevalence of treatments used between stiff and non-stiff TKA groups and their financial impact. METHODS: An observational cohort study was conducted using a large database. A total of 12,942 patients who underwent unilateral primary TKA from January 1, 2017, to December 31, 2017, were included. Stiffness after TKA was defined as manipulation under anesthesia and a diagnosis code of stiffness or ankylosis, and subsequent diagnosis and procedure codes were used to identify the prevalence and financial impact of multiple common treatment options. RESULTS: The prevalence of stiffness after TKA was 6.1%. Stiff patients were more likely to undergo physical therapy, medication, bracing, alternative treatment, clinic visits, and reoperation. Revision surgery was the most common reoperation in the stiff TKA group (7.6%). The incidence of both arthroscopy and revision surgery were higher in the stiff TKA population. Dual component revisions were costlier for patients who had stiff TKAs ($65,771 versus $48,287; P < .05). On average, patients who had stiffness after TKA endured costs from 1.5 to 7.5 times higher than the cost of their non-stiff counterparts during the 2 years following index TKA. CONCLUSION: Patients who have stiffness after primary TKA face significantly higher treatment costs for both operative and nonoperative treatments than patients who do not have stiffness.

Chlorpyrifos induces neuronal cell death via both oxidative stress and Akt activation downstream-regulated CHOP-triggered apoptotic pathways.

Chlorpyrifos (CPF) is one of the most abundant and widely used organophosphate pesticides for agricultural, industrial, and household purposes in the world. Epidemiological studies have reported that CPF can induce neurotoxic impairments in mammalian, which is linked to an important risk factor for development of neurodegenerative diseases (NDs). However, limited information is available on CPF-induced neurotoxicity, with the underlying exact mechanism remains unclear. In this study, CPF exposure (10-400 µM) significantly reduced Neuro-2a cell viability and induced apoptotic events, including the increase in caspase-3 activity, apoptotic cell population, and cleavage of caspase-3/-7 and PARP. Exposure of Neuro-2a cells to CPF also triggered CHOP activation. Transfection with CHOP-specific siRNA markedly suppressed the expression of CHOP, and attenuated cytotoxicity and apoptotic events in CPF-exposed Neuro-2a cells. Furthermore, CPF exposure obviously evoked the phosphorylation of Akt as well as ROS generation in a time-dependent manner. Pretreatment with LY294002 (an Akt inhibitor) effectively attenuated the CPF-induced Akt phosphorylation, CHOP activation, and apoptotic events, but not that ROS production. Of note, buffering the ROS generation with antioxidant N-acetylcysteine effectively prevented the CPF-induced ROS generation, CHOP activation, and apoptotic events, but not that the Akt phosphorylation. Collectively, these findings indicate that CPF exposure exerts neuronal cytotoxicity via the independent pathways of ROS generation and Akt activation downstream-regulated CHOP-triggered apoptosis, ultimately leading to neuronal cell death.

The trend and future projection of technology-assisted total knee arthroplasty in the United States.

BACKGROUND: As technology-assisted surgery has boosted in the last decades, we aimed to investigate the factors affecting adoption and to predict the future utilization of technology among patients who underwent total knee arthroplasty (TKA). METHODS: Patients underwent TKA in 2017-2019 in the MarketScan Database were included. Percentage of technology-assisted surgery was calculated. Multivariable logistic regression models were performed to analyse the factors and make the prediction. RESULTS: Of 112,161 TKA procedures, 7.2% were technology-assisted. The proportion of technology-assisted TKA is expected to reach 50% by 2032. The West showed the highest proportion of technology-assisted TKA (12.3%), while the South had the lowest (5.7%). Over time, the Midwest showed the greatest increase in technology adoption (OR = 1.26 compared to the Northeast, 95% CI [1.15, 1.38]). CONCLUSIONS: Technology adoption rate of TKA will continue to increase for the next 20 years in the United States with a slight geographical variation.

Gender Homophily in Interphysician Referrals to Surgeons.

INTRODUCTION: The literature on gender homophily has mostly been focused on patient-physician relationship but not on interprofessional referrals. The goal of this study is to quantify interphysician gender homophily of referring physicians in surgical referrals. METHODS: An observational study of the referral data at a large academic center was performed. Patients referred through Epic to the department of general surgery from January 2016 to October 2019 were included. The primary end point was gender homophily and the primary independent variable was referring physician gender. Gender homophily was defined as greater than expected rates of gender concordance. Gender concordance was defined when referring physicians have the same gender as receiving surgeons. The expected concordance rate was defined as the availability of gender-concordant surgeons in the population. Absolute homophily is the difference between observed and expected concordance rates, whereas relative homophily is the ratio between observed and expected concordance rates. RESULTS: A total of 25,271 patient referrals from 2625 referring physicians to 91 surgeons were analyzed. The overall observed concordance rate for the entire study population was 55.3% and was 31.7% among female physicians and 82.4% among male physicians. Compared to the expected concordance rate, the absolute gender homophily among all female physicians was +7.2% or a relative homophily of 1.29%. In contrast, the absolute gender homophily among all male physicians was +6.9% or a relative homophily of 1.09%. CONCLUSIONS: Gender homophily exists in interprofessional referrals. Although referral decisions are presumably based solely on clinical factors, referrals can be affected by subjective biases.

Involvement of AMPKα and MAPK-ERK/-JNK Signals in Docetaxel-Induced Human Tongue Squamous Cell Carcinoma Cell Apoptosis.

Cancers of the oral cavity can develop in the anatomic area extending from the lip, gum, tongue, mouth, and to the palate. Histologically, about 85-90% of oral cavity cancers are of the type squamous cells carcinomas (SCCs). The incidence of oral tongue SCC is higher in the tongue than any other anatomic area of the oral cavity. Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The results showed that docetaxel (10-300 nM) induced cytotoxicity and caspase-3 activity in SAS cells. Moreover, docetaxel (100 nM) promoted the expression of apoptosis-related signaling molecules, including the cleavages of caspase-3, caspase-7, and poly (ADP-ribose) polymerase (PARP). In mitochondria, docetaxel (100 nM) decreased the mitochondrial membrane potential (MMP) and Bcl-2 mRNA and protein expression and increased cytosolic cytochrome c protein expression and Bax mRNA and protein expression. In terms of mitogen-activated protein kinase (MAPK) and adenosine monophosphate-activated protein kinase (AMPK) signaling, docetaxel increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK), and p-AMPKα protein expression but not p-p38 protein expression. Moreover, the increase in caspase-3/-7 activity and Bax protein expression and decreased Bcl-2 protein expression and MMP depolarization observed in docetaxel-treated SAS cells could be reversed by treatment with either SP600125 (a JNK inhibitor), PD98059 (an MEK1/2 (mitogen-activated protein kinase kinase 1/2) inhibitor), or compound c (an AMPK inhibitor). The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth.

Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals.

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic ß cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate ß-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-ß that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.