Neuronal survival factor VGF promotes chemoresistance and predicts poor prognosis in lung cancers with neuroendocrine feature.

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

Discovery of novel aminosaccharide-based sulfonamide derivatives as potential carbonic anhydrase II inhibitors.

In this paper, a new class of novel sulfonamides incorporating aminosaccharide tails were designed and synthesized based on the sugar-tail approach. Then, all the novel compounds were evaluated for their inhibitory activities against three carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes (hCA I, hCA II and hCA IX). Interestingly, effective inhibition of these three CA isoforms were observed, especially the glaucoma associated isoform hCA II. It is worth noting that these glycoconjugated sulfonamide derivatives also showed better CA inhibitory effects compared to the initial segment carzenide. Among them, compound 8d was the most effective inhibitor with IC50 of 60 nM against hCA II. Subsequent physicochemical properties studies showed that all compounds have good water solubility and neutral pH values in solutions. And these important physicochemical properties make target compounds acquire obvious advantages in the preparation of topical and nonirritating antiglaucoma drugs. Moreover, the target compounds showed lower corneal cytotoxicity than acetazolamide (AAZ) and good metabolic stability in vitro. In addition, molecular docking studies confirmed the interactions between aminosaccharide fragment and hydrophilic subpocket of hCA II active site were crucial for the enhanced CA inhibitory activity. Taken together, these results suggested 8d would be a promising lead compound for the development of topical antiglaucoma CAIs.

Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Induction of Heat Shock Protein Genes is the Hallmark of Egg Heat Tolerance in Agasicles hygrophila (Coleoptera: Chrysomelidae).

Insects are ecotothermic organisms. Their development, survival, reproduction as well as distribution and abundance are affected by temperature. Heat shock protein (HSP) gene expression is closely associated with temperature variation and influences the adaptation of organisms to adverse environments. The beetle Agasicles hygrophila has successfully been used for biological control of the invasive plant alligator weed (Alternanthera philoxeroides). As A. hygrophila populations are substantially inhibited by high temperatures in the summer, increasing global temperatures may limit the efficacy of this control agent. We previously established that A. hygrophila eggs have low tolerance to heat and this factored into the decreased numbers of A. hygrophila beetles at temperatures of 37.5°C and above. Here, we identified 26 HSP genes in A. hygrophila and examined the relationship between the transcript levels of these genes and heat tolerance. The temperature at which the expression of these 21 HSP genes peaked (Tpeak) was 37.5°C, which is in line with the limit of the high temperatures that A. hygrophila eggs tolerate. Therefore, we speculate that the Tpeak of HSP gene expression in eggs indicates the upper limit of temperatures that A. hygrophila eggs tolerate. This study identifies HSP genes as potential robust biomarkers and emphasizes that determining species' heat tolerance in their natural habitats remains an important consideration for biocontrol. HSP gene expression data provide information about a species' heat tolerance and may be used to predict its geographical distribution.

Heat sensitivity of eggs attributes to the reduction in Agasicles hygrophila population.

Agasicles hygrophila has been introduced worldwide as a control agent for the invasive weed Alternanthera philoxeroides. However, global warming has potential impact on its controlling efficacy. The aim of this research was to explore the primary factors responsible for the greatly reduced A. hygrophila population in hot summers. To imitate the temperature conditions in summers, different developmental stages of A. hygrophila were treated with high temperatures from 32.5 °C to 45 °C for 1-5 h. Based on the survival rate, the heat tolerance of each developmental stage was ranked from lowest to highest as follows: egg, 1st, 2nd, 3rd instar larva, adult and pupa. Eggs showed the lowest heat tolerance with 37.5 °C as the critical temperature affecting larval hatching. Heat treatment of the A. hygrophila eggs at 37.5 °C for 1 h decreased the hatch rate to 24%. Our results indicated that when compared with the control at 25 °C, 1 h treatment at 37.5 °C prolonged the duration of the egg stage, shortened the duration of oviposition and total longevity, and changed the reproductive pattern of A. hygrophila. The net reproductive rate, intrinsic rate and finite rate were all significantly reduced. The results suggest that low heat tolerance of the eggs was the major factor responsible for the reduction of A. hygrophila populations, and the key temperature was 37.5 °C. Therefore, appropriate measures should be taken to protect eggs in order to maintain the efficacy of A. hygrophila in the biological control of A. philoxeroides in hot summers.

Response to Short-Term Cold Storage for Eggs of Agasicles hygrophila (Coleoptera: Chrysomelidae), a Biological Control Agent of Alligator Weed Alternanthera philoxeroides (Caryophyllales: Amaranthaceae).

The alligator weed flea beetle, Agasicles hygrophila Selman & Vogt (Coleoptera: Chrysomelidae) has been used very successfully for the biological control of the widely-distributed invasive weed Alternanthera philoxeroides (Mart.) Griseb (Caryophyllales: Amaranthaceae). In order to extend the 'shelf life' of natural enemies released in biological control programs, cold storage has proven to be a valuable commercial procedure. To determine a suitable low temperature for storage of A. hygrophila, we conducted short-term cold storage treatments of eggs (4°C for 0.5, 1, 2, 5 d, and 7.5, 10, 15°C for 5 d and a control of 25°C; all eggs were returned to 25°C after the treatments). We evaluated the effects of these treatments on the subsequent fitness of the populations based on a demographic analysis using group-reared age-stage two-sex life tables. For 5 d storage, temperatures below 10°C had lethal effects, which were also observed at 4°C for 2 d storage. Storage at 4°C for 0.5 d did not affect the fitness of A. hygrophila, but it did not prolong the developmental time. Storage at 10°C for 5 d significantly decreased rates of population increase compared with 25°C. A. hygrophila stored at 15°C for 5 d had similar age-(stage) specific survival rates, rates of population increase, increased longevity and reproductive capability to the controls at 25°C. It is concluded that there were no significant fitness costs after 5 d storage at 15°C, which is therefore potentially a suitable storage temperature for A. hygrophila eggs.