Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report ...that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.
Capitalizing on the inherent multiplexing capability of AsCpf1, we developed a multiplexed, high-throughput screening strategy that minimizes library size without sacrificing gene targeting ...efficiency. We demonstrated that AsCpf1 can be used for functional genomics screenings and that an AsCpf1-based multiplexed library performs similarly as compared to currently available monocistronic CRISPR/Cas9 libraries, with only one vector required for each gene. We construct the smallest whole-genome CRISPR knock-out library, Mini-human, for the human genome (n = 17,032 constructs targeting 16,977 protein-coding genes), which performs favorably compared to conventional Cas9 libraries.
The present study demonstrated the protective effects of low-molecular-weight adipose-derived stem cell-conditioned medium (LADSC-CM) in a mouse model of dry eye syndrome. Mice subjected to ...desiccating stress and benzalkonium chloride had decreased tear secretion, impaired corneal epithelial tight junction with microvilli, and decreased conjunctival goblet cells. Topical application of adipose-derived stem cell-conditioned medium (ADSC-CM) stimulated lacrimal tear secretion, preserved tight junction and microvilli of the corneal epithelium, and increased the density of goblet cells and MUC16 expression in the conjunctiva. The low-molecular-weight fractions (< 10 kDa and < 3 kDa) of ADSC-CM (LADSC-CM) provided better protections than the > 10 kDa or > 3 kDa fractions of ADSC-CM. In the in vitro study, desiccation for 10 min or hyperosmolarity (490 osmols) for 24 h caused decreased viability of human corneal epithelial cells, which were reversed by LADSC-CM. The active ingredients in the LADSC-CM were lipophobic and stable after heating and lyophilization. Our study demonstrated that LADSC-CM had beneficial effects on experimental dry eye. It is worthy of further exploration for the active ingredient(s) and the mechanism.
Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Here, studying clonal evolution of tumor cells derived from ...human pancreatic tumors, we demonstrate that in vitro cultures and in vivo tumors are maintained by a common set of tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of adaptive responses to therapeutics, we uncovered a multitude of functionally heterogeneous subpopulations of cells with differential degrees of drug sensitivity. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying functionally diverse subpopulations. Molecular annotation of gemcitabine-naive clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy, representing a potential biomarker to stratify patients with pancreatic cancer.
Display omitted
•Lineage tracing reveals in vitro and in vivo tumors are maintained by common clones•Deep lineage dynamics characterization enables generation of clonal replica tumors•Pancreatic CRTs unmask functional tumor heterogeneity in response to therapeutics•Gemcitabine-naive subclonal gene signature predicts chemotherapy response
High-complexity lineage tracing shows that tumors growing in different environments are maintained by a common set of tumorigenic cells that enables the generation of clonal replica tumors (CRTs). Applying CRTs, Seth et al. unmask functional heterogeneity in response to therapeutics and identify a signature that predicts chemoresistance in pancreatic cancer.
COVID-19 is threatening human health worldwide but no effective treatment currently exists for this disease. Current therapeutic strategies focus on the inhibition of viral replication or using ...anti-inflammatory/immunomodulatory compounds to improve host immunity, but not both. Traditional Chinese medicine (TCM) compounds could be promising candidates due to their safety and minimal toxicity. In this study, we have developed a novel
bioinformatics workflow that integrates multiple databases to predict the use of honeysuckle (
) and Huangqi (
) as potential anti-SARS-CoV-2 agents. Using extracts from honeysuckle and Huangqi, these two herbs upregulated a group of microRNAs including
,
, and
, which are critical to reduce the pathogenesis of SARS-CoV-2. Moreover, these herbs suppressed pro-inflammatory cytokines including IL-6 or TNF-α, which were both identified in the cytokine storm of acute respiratory distress syndrome, a major cause of COVID-19 death. Furthermore, both herbs partially inhibited the fusion of SARS-CoV-2 spike protein-transfected BHK-21 cells with the human lung cancer cell line Calu-3 that was expressing ACE2 receptors. These herbs inhibited SARS-CoV-2 M
activity, thereby alleviating viral entry as well as replication. In conclusion, our findings demonstrate that honeysuckle and Huangqi have the potential to be used as an inhibitor of SARS-CoV-2 virus entry that warrants further
analysis and functional assessment of miRNAs to confirm their clinical importance. This fast-screening platform can also be applied to other drug discovery studies for other infectious diseases.
Apocrine hidrocystomas are benign cystic tumors resulting from apocrine sweat glands’ proliferation. They typically present as solitary, slow-growing nodules at the head and neck, especially in the ...periorbital cutaneous region. We present a case of periorbital apocrine hidrocystoma in a 22-year-old woman that was treated as chalazion previously. Besides the hallmark histopathological findings of apocrine hidrocystoma, IgG4 plasma cell infiltration of the cystic wall was also found. The ratio of IgG4-to-IgG-positive plasma cells was high, whereas serum IgG4 was within the standard limit. This is, to date, the only probable IgG4-related ophthalmic disease associated with apocrine hidrocystoma.
Alopecia is one of the most common adverse effects of chemotherapy. It reduces the patient's self-esteem and quality of life and the effect of therapy. Scalp cooling is the only verified current ...method for prevention but success is not guaranteed, particularly after receiving anthracycline-based combinations. Low-level light therapy has been clinically proven to inhibit the progress of androgenic alopecia. A previous study using human subjects shows limited benefits for low-level light therapy for patients who suffer chemotherapy-induced alopecia but an increase in the number of probes and the optimization of light sources may improve the efficacy. This study determines the efficacy of low-level light therapy for the prevention of chemotherapy-induced hair loss for patients with breast cancer using a randomized controlled trial.
One hundred six eligible breast cancer patients were randomly distributed into a low-level light therapy group and a control group, after receiving chemotherapy. Subjects in the low-level light therapy group received 12 courses of intervention within 4 weeks. Subjects in the control group received no intervention but were closely monitored. The primary outcome is measured as the difference in the hair count in a target area between the baseline and at the end of week 4, as measured using a phototrichogram (Sentra scalp analyzer). The secondary outcomes include the change in hair count at the end of week 1, week 2, and week 3 and hair width at the end of week 1, week 2, week 3, and week 4, as measured using a phototrichogram, and the change in distress, the quality of life, and self-esteem due to chemotherapy-induced alopecia, at the end of week 4, as measured using a questionnaire.
This study improves cancer patients' quality of life and provides clinical evidence.
Registered at ClinicalTrials.gov- NCT05397457 on 1 June 2022.
Alzheimer disease (AD), a common form of dementia, shares several clinical and pathologic features with age-related macular degeneration (AMD). Epidemiologic reports on the association of AMD with ...subsequent dementia or AD are inconsistent.
Systematic review and meta-analysis.
The Meta-analysis of Observational Studies in Epidemiology reporting guidelines were applied. The Newcastle-Ottawa Scale was used to evaluate the risk of bias in the included cohort studies that examined the association of AMD with subsequent dementia or AD. We estimated the pooled hazard ratios (HRs) of dementia or AD using random effects model meta-analysis and subgroup analysis on different follow-up periods, AMD subtype, gender, age, study design, and methods to ascertain dementia or AD.
A total of 8 223 581 participants were included in 8 studies published during 2000-2021. The meta-analysis showed that AMD was significantly associated with subsequent dementia (pooled HR 1.22, 95% CI 1.01-1.47) or AD (pooled HR 1.21, 95% CI 1.03-1.43). Our secondary analysis revealed that the association was more noticeable in dry AMD than wet AMD.
Patients with AMD have higher risks of developing dementia or AD, and therefore identifying related comorbidities and retinal biomarkers is much warranted for older adults with AMD in ophthalmologic practice.
In this study, we investigated the impact of inserting an interfacial layer (IL) between the InZnO channel and ZrO2/HfO2 superlattice (SL) ferroelectric (FE) gate-stack on the performance and ...stability of highly scaled FE thin-film transistors (FeTFTs). FeTFTs with various channel lengths (50-750 nm) were characterized to reveal the impact of two IL (i.e., TiO2 and Al2O3) on device characteristics. All the memory window (MW) contours of FeTFTs with a pulsewidth of 1 ms-100 ns and an amplitude of 2.5-5 V have been investigated. The FeTFT with TiO2 IL demonstrated impressive stability in MW (<inline-formula> <tex-math notation="LaTeX">\boldsymbol {\Delta } </tex-math></inline-formula> MW/MW<inline-formula> <tex-math notation="LaTeX">_{{1}\text {st cy}\text {cle}}~\boldsymbol {\le } ~3.6 </tex-math></inline-formula>%) up to 108 cycles for a program/erase voltage of <inline-formula> <tex-math notation="LaTeX">\boldsymbol {\pm }3 </tex-math></inline-formula> V and pulsewidth of <inline-formula> <tex-math notation="LaTeX">1~\boldsymbol {\mu } </tex-math></inline-formula> s. It was suggested that the FeTFT with a higher dielectric constant <inline-formula> <tex-math notation="LaTeX">(k) </tex-math></inline-formula> TiO2 IL may reduce the electrical field and depolarization field at the interface between the channel and gate dielectric, as well as improve interfacial quality, thereby enhancing the reliability of FeTFTs.
Epidermal growth factor receptor (EGFR) mutations related to gefitinib responsiveness in non-small cell lung cancer have been found recently. Detection of EGFR mutations has become an important issue ...for therapeutic decision-making in non-small cell lung cancer.
Mutational analysis of the kinase domain of EGFR coding sequence was done on 101 fresh frozen tumor tissues from patients without prior gefitinib treatment and 16 paraffin-embedded tumor tissues from patients treated with gefitinib. Detection of phosphorylated EGFR by immunoblot was also done on frozen tumor tissues.
The 101 non-small cell lung cancer tumor specimens include 69 adenocarcinomas, 24 squamous cell carcinomas, and 8 other types of non-small cell lung cancers. Mutation(s) in the kinase domain (exon 18 to exon 21) of the EGFR gene were identified in 39 patients. All of the mutations occurred in adenocarcinoma, except one that was in an adenosquamous carcinoma. The mutation rate in adenocarcinoma was 55% (38 of 69). For the 16 patients treated with gefitinib, 7 of the 9 responders had EGFR mutations, and only 1 of the 7 nonresponders had mutations, which included a nonsense mutation. The mutations seem to be complex in that altogether 23 different mutations were observed, and 9 tumors carried 2 mutations.
Data from our study would predict a higher gefitinib response rate in lung adenocarcinoma patients in Chinese and, possibly, other East Asian populations. The tight association with adenocarcinoma and the high frequency of mutations raise the possibility that EGFR mutations play an important role in the tumorigenesis of adenocarcinoma of lung, especially in East Asians.
PDF
