Sustainability performance evaluation involving internal resource imbalance: an additive aggregation network DEA approach.

Environmental pollution, as a byproduct of economic growth, causes negative pressure on human health. Its sustainability management performance is closely bound up with the ecological carrying capacity. Due to the limited carrying capacity of ecosystems to pollutants, the hidden costs of pollutants may increase when pollutants flow and spread. This is an external manifestation of the internal resource imbalance within the ecosystem, restricting the sustainability of economy and environment and overlooked by most studies that target sustainability performance evaluation. Thus, this study considers the internal resource imbalance during the sustainability performance evaluation for the first time in the context of the interaction among economy, environment, and human health, by constructing a production-treatment-health framework, proposing an internal resource imbalance index and developing an additive aggregation network data envelopment analysis model with the semidefinite programming technology. This study takes 30 Chinese provinces from 2012 to 2017 as the research objects and confirms the effectiveness of sustainability management in terms of water pollution purification and water ecological construction.

Clinical outcomes and risk factor of immune checkpoint inhibitors-related pneumonitis in non-small cell lung cancer patients with chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is the most common co-morbidity associated with non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors related pneumonitis (CIP) is a common immune-related adverse event that can be life-threatening. The study aims to evaluate the association of COPD with the incidence and outcome of CIP in NSCLC patients receiving immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: We retrospectively collected data from 122 patients diagnosed with NSCLC and treated with ICIs in our department. Baseline pulmonary function was performed in the whole cohort. The incidence, risk factors, treatment and outcome of CIP patients were evaluated. Furthermore, the efficacy of ICIs in patients with COPD was analyzed. RESULTS: Nineteen patients (15.5%, 19/122) developed CIP during ICIs treatment, most patients with CIP were grade 1-2, and the incidence of CIP was comparable in patients with COPD and those without COPD (18.0% vs. 13.1%, P = 0.618). In addition, an increasing trend in the incidence of CIP among patients with pulmonary fibrosis on baseline chest CT scans (27.3% vs. 13.0%, P = 0.093). There is a longer progression-free survival in COPD patients than the non-COPD patients. CONCLUSION: Coexisting COPD did not predict the higher risk of CIP in NSCLC treated with ICIs therapy. Nevertheless, pre-existing pulmonary fibrosis on CT scan may increase the risk of CIP, close monitoring is advised in these patients during ICIs.

Study on chronic toxicity of rhubarb extract in Sprague-Dawley rats.

Objective: The purpose of this study was to evaluate the safety of rhubarb extract. Methods: SD rats were treated with rhubarb extract at 0, 101, 405 and 1620 mg/kg/day for 52 weeks. food consumption and body weights were recorded. Blood and urine samples were collected for serum biochemical evaluation and urinalysis, and organ tissues were collected for histopathological examination. Results: The rats of 1620 mg/kg group developed diarrhea symptoms with dark brown loose stool after exposure; decreased body weight and increased food consumption were observed in the 1620 mg/kg and 405 mg/kg groups; urine WBC and NIT was significantly increased in the male and female rats of 1620 mg/kg group, and the urine pH was decreased in male rats of 1620 mg/kg group; renal tubular pigmentation was observed in the 1620 mg/kg group. Conclusion: The NOAEL of rhubarb extract on chronic toxicity (52 weeks) of Sprague-Dawley rats was 101 mg/kg in female and 94 mg/kg in male, and the LOAEL was 408 mg/kg in female and 381 mg/kg in male. The target organ of toxicity was the kidney, and the target cells was tubular epithelial cells.

New NNN pincer copper complexes as potential anti-prostate cancer agents.

Eleven novel NNN Cu(II) complexes supported by a tridentate bis(imidazo[1,2-α]pyridin-2-yl)pyridine ligand were synthesized and characterized by elemental analysis, HRMS, and X-ray determination. Target prediction and docking studies indicated that these pincer complexes formed hydrogen bonds with Asp33 and Gly35 of Cathepsin D protein, which is highly associated with prognosis of advanced prostate cancer. Furthermore, they exhibited anti-proliferation activity in both androgen-sensitive and androgen-insensitive prostate cancer cells according to WST-1 assay results. Mechanistic study showed that pincer complexes arrested cell cycle progression at G0/G1 phase and inhibited Cathepsin D regulated signaling pathways. Most importantly, new pincer copper complexes significantly inhibited xenograft prostate cancer growth along with a promising in vivo safety profile. In summary, these results suggest the applicability of the developed novel pincer copper complexes as promising anticancer agents for prostate cancer treatment.

Efficacy and Safety of PD-L1 Inhibitors plus Chemotherapy versus Chemotherapy Alone in First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer: A Retrospective Real-World Study.

Background: Most patients with small-cell lung cancer (SCLC) have extensive-stage (ES) disease with a poor prognosis. Immunotherapy has shown good therapeutic effects in the treatment of ES-SCLC. We performed a real-world retrospective study to evaluate the safety and efficacy of PD-L1 inhibitors plus chemotherapy in patients with ES-SCLC. Method: A total of 224 patients diagnosed with ES-SCLC between March 2017 and April 2021 were included, of which 115 received only etoposide-platinum (EP) chemotherapy,and 109 received programmed cell-death ligand 1 (PD-L1) inhibitors and EP. Results: Immune checkpoint inhibitors (ICIs) plus platinum were associated with a significant improvement in overall survival (OS), with a hazard ratio (HR) of 0.60 (95% CI, 0.42-0.85; P=0.0054); median OS was 19 months in the ICIs plus EP group vs. 12 months in the EP group. The median progression-free survival (PFS) was 8.5 and 5.0 months, respectively (HR for disease progression or death, 0.42; 95% CI, 0.31-0.57; P < 0.0001). Male patients <65 years old, Stage IV, PS 0-1, without liver and brain metastasis had a better OS in the ICIs plus EP group than the EP group. The PFS and OS in the durvalumab plus chemotherapy group were insignificantly longer than that of the atezolizumab plus chemotherapy group. Any adverse effects (AEs) of grade 3 or 4 occurred in 50 patients (45.9%) in the ICIs plus EP group and 48 patients (41.7%) in the EP alone group. The most common immune-related AEs (irAEs) were immune hypothyroidism events (17.1%, 7/41), immune dermatitis (9.8%, 4/41), and immune pneumonia (9.8%, 4/41) in the durvalumab plus platinum-etoposide group. Immune liver insufficiency (10.3%, 7/68) and immune hypothyroidism (8.8%, 6/68) were the most common irAEs in the atezolizumab plus platinum-etoposide group. Conclusion: This study shows that adding PD-L1 inhibitors to chemotherapy can significantly improve PFS and OS in patients with ES-SCLC and demonstrates its safety without additional AEs.

Tibetan Medicine Shi-Wei-Gan-Ning-San Alleviates Carbon Tetrachloride-Induced Chronic Liver Injury by Inhibiting TGF-ß1 in Wistar Rats.

Background: Shi-Wei-Gan-Ning-San (SWGNS) is a classic Tibetan prescription, which has obvious clinical effects in the treatment of viral hepatitis, fatty liver, liver fibrosis, liver cirrhosis, liver cancer, and other liver injuries. However, animal studies and mechanism studies are still lacking. This study aimed to investigate its hepatoprotective efficacy and pharmacological mechanism in animal experiments. Methods: Chronic liver injury was induced by oral administration of carbon tetrachloride (CCl4) in Wistar rats for 13 weeks. SWGNS was administered orally to rats at doses of 235, 705, and 1410 mg/kg for 13 weeks. Blood samples were collected for biochemical, ELISA, and radioimmunoassay. Livers were harvested for H&E and immunohistochemical staining. The major constituents of SWGNS were analyzed by HPLC. In vitro experiments were used to explore the protective effect of Crocin on BRL-3A in the environment of H2O2. Results: SWGNS reversed weight loss is induced by CCl4. Serum assays showed that SWGNS reduced CCl4-induced alanine aminotransferase, aspartate aminotransferase, total bilirubin, and γ-glutamyltransferase levels and increased the total protein and albumin levels. Histopathological evaluation showed that SWGNS alleviated hepatic steatosis, fibrosis, and inflammation. Furthermore, SWNGS reduced CCl4-induced elevations of TGF-ß1, hyaluronic acid, laminin, and collagen IV in serum and reduced the high expression of α-SMA in tissues. Moreover, Crocin I and II are the main components of SWGNS. Crocin attenuated the damaging effects of H2O2 on BRL-3A. Conclusions: In conclusion, SWGNS alleviated CCl4-induced chronic liver injury by inhibiting the TGF-ß1 pathway. This plays an important role in promoting traditional Tibetan medicine in clinical practice.

Acute and Subchronic Oral Toxicity of Anthraquinone in Sprague Dawley Rats.

OBJECTIVE: This study was conducted to evaluate the acute and subchronic toxicity of anthraquinone. An acute toxicity test was performed in female Sprague Dawley (SD) rats, and the oral median lethal dose (LD50) of anthraquinone was estimated to be >5000 mg/kg body weight (BW). In the subchronic study, groups of 10 male and 10 female rats were dosed with anthraquinone by gavage at 0, 1.36, 5.44, 21.76, and 174.08 mg/kg BW, 7 days/week for 90 days followed by a recovery period of 28 days. No appreciable toxic-related changes were observed in the 1.36 mg/kg BW group. When the animals received 5.44 mg/kg BW or more of anthraquinone, hyaline droplet accumulation in the renal tubules was observed in both the male and female rats, and anemia was observed in the females. When the anthraquinone dose reached 174.08 mg/kg BW, mild hepatocellular hypertrophy around the central vein of the hepatic lobule and hypothyroidism were observed in the female rats. During the recovery period, changes in clinical symptoms and parameters were considerably alleviated. Based on the results of this study, the no observed adverse effect level (NOAEL) for anthraquinone in rats was set at 1.36 mg/kg BW, and the lowest observed adverse effect level (LOAEL) was 5.44 mg/kg BW.

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity.

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.

Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation.

Background: Limited treatment outcome data is available for advanced non-small cell lung cancer (NSCLC) patients with BRAF V600E mutations. In this multicenter study, we describe therapeutic options and survival outcomes for patients with mutated BRAF V600E. Method: This was a retrospective study in which BRAF V600E-mutated advanced NSCLC patients were retrospectively recruited between January 2015 and December 2021 and had their clinical characteristics, co-mutations, and treatment efficacy assessed. Results: Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation was more prevalent in men (52.8%). In addition, 96.2% of the patients had adenocarcinoma, and most (96.2%) received first-line therapy (23.5% anti-BRAF), with a progression-free survival (PFS) and overall survival (OS) of 10.0 [95% confidence interval (CI): 1.5-36.0 months] and 24.0 months [95% CI: 3.0-53.0 months], respectively. Twenty-three patients (43.4%) received second-line treatment (39.1% anti-BRAF), and PFS and OS were 5.0 [95% CI: 1.0-21.0 months] and 13.0 months [95% CI: 1.5-26.0 months], respectively. BRAF and MEK-targeted therapy (dabrafenib plus trametinib) produced longer PFS compared with that of chemotherapy with or without bevacizumab as a first-line (NA vs. 4.0 months, P = 0.025) or second-line therapy (6.0 vs. 4.6 months, P = 0.017). NSCLC patients harboring driver oncogene mutations such as BRAF V600E, EGFR, or ALK should be treated using targeted therapies. Concurrent TP53 mutations were the most common, affecting 11.3% (n = 6) of the patients, followed by EGFR 19 Del (n = 5). Patients with concurrent mutations had shorter PFS (9.0 vs. 10.0 months, P = 0.875) and OS (14.0 vs. 15.0 months, P = 0.555) than those without these mutations. Conclusion: These results suggest that combined BRAF- and MEK-targeted therapy is effective in BRAF V600E-mutated advanced NSCLC patients. Dabrafenib and trametinib re-challenge is also an option for patients with BRAF V600E-mutated NSCLC.

The Novel Function of Unsymmetrical Chiral CCN Pincer Nickel Complexes as Chemotherapeutic Agents Targeting Prostate Cancer Cells.

We report that the pincer nickel complexes display prostate cancer antitumor properties through inhibition of cell proliferation. Notably, they display better antitumor properties than cisplatin. Mechanistic studies reveal that these pincer nickel complexes trigger cell apoptosis, most likely due to cell cycle arrest. Interestingly, these complexes also inhibit androgen receptor (AR) and prostate-specific antigen (PSA) signaling, which are critical for prostate cancer survival and progression. Our study reveals a novel function of pincer nickel complexes as potential therapeutic drugs in prostate cancer.

Measuring environmental efficiency and technology inequality of China's power sector: methodological comparisons among data envelopment analysis, free disposable hull, and super free disposable hull models.

China's power sector has received great research attention because of its large energy consumption and CO2 emissions. This study assesses the environmental efficiency and technology inequality of China's power sector from 2008 to 2017. Methodologically, this study proposes a non-radial FDH (free disposable hull) model and a super non-radial FDH model. The non-radial FDH model relaxes the convex assumption and captures all inefficiencies of inputs, desirable output and undesirable output. The super non-radial model is capable of discriminating efficient power sectors and always has feasible solutions. We also compare their performance with the non-radial data envelopment analysis (DEA) model. The main conclusions are summarized as follows: First, the environmental efficiency of China's power sector has experienced steady growth; the power sectors in the east region outperform those in other regions. Second, the proposed FDH models are more applicable and reliable than the non-radial DEA model in efficiency measurement of China's power sector, due to the indivisibility of labor. Third, there has been growing technology inequality and the main driving factor determining technology inequality is the inter-region efficiency Gini coefficient. To improve environmental efficiency and eliminate technology inequality, the government should mainly solve the issue of excessive labor input and establish a free technology market for technology trading.

Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications.

As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has been successfully treated with tyrosine kinase inhibitors (TKIs). However, resistance to osimertinib, a third-generation TKI, can be difficult to overcome in this small subset of patients and is attributed to secondary resistant mutations. Here, we report a case of acquired EGFR L858R/L718Q mutation with advanced NSCLC that resistant to osimertinib, which was successfully overcome using dacomitinib. CASE PRESENTATION: A 64-year-old non-smoker woman was diagnosed with stage IV non-small cell lung adenocarcinoma with EGFR L858R mutation and brain metastasis in November 2018. Treatment with gefitinib and gamma knife radiosurgery was started as the first-line treatment. After 7 months, she experienced disease progression with increased primary lung lesions and switched to osimertinib based on an acquired EGFR T790M mutation. After another 4 months, the disease progressed, and she was switched to chemotherapy. During chemotherapy, brain MRI showed an increasing number of parietal lobe metastases. Hence, gamma knife radiosurgery was performed again. After 12 months, the disease progression resumed, and an EGFR L718Q mutation was found on biopsy. The patient was then challenged with dacomitinib, and the disease was partially responsive and under control for 6 months. CONCLUSION: Currently, there are no established guidelines for overcoming osimertinib resistance caused by the L718Q mutation. The acquired EGFR L718Q mutation in subsequent resistance to osimertinib could be overcome using dacomitinib, indicating a promising treatment option in the clinic.

A Large Real-World Study on the Effectiveness of the Combined Inhibition of EGFR and MET in EGFR-Mutant Non-Small-Cell Lung Cancer After Development of EGFR-TKI Resistance.

BACKGROUND: MET proto-oncogene amplification (amp) is an important mechanism underlying acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the optimal treatment strategy after acquiring MET-amp-mediated EGFR-TKI resistance remains controversial. Our study compared three treatment strategies for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who were detected with MET-amp at EGFR-TKI progression using next-generation sequencing. METHODS: Of the 70 patients included in the study, 38 received EGFR-TKI + crizotinib, 10 received crizotinib monotherapy, and 22 received chemotherapy. Clinical outcomes and molecular profiles were analyzed. RESULTS: The objective response rate was 48.6% for EGFR-TKI + crizotinib group, 40.0% for crizotinib monotherapy group, and 18.2% for chemotherapy group. Patients who received EGFR-TKI + crizotinib had significantly longer progression-free survival than those who received crizotinib or chemotherapy (5.0 vs. 2.3 vs. 2.9 months, p = 0.010), but overall survival was comparable (10.0 vs. 4.1 vs. 8.5 months, p = 0.088). TP53 mutation (58.5%) and EGFR-amp (42.9%) were frequent concurrent mutations of the cohort. Progression-free survival was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs. 2.3 vs. 2.9 months, p = 0.009) or EGFR-amp (n = 13) (5.0 vs. 1.2 vs. 2.4 months, p = 0.016) in the EGFR-TKI + crizotinib group than the other two regimen. Potential acquired resistance mechanisms to EGFR-TKI + crizotinib included EGFR-T790M (n = 2), EGFR-L718Q (n = 1), EGFR-S645C (n = 1), MET-D1228H (n = 1), BRAF-V600E (n = 1), NRAS-Q61H (n = 1), KRAS-amp (n = 1), ERBB2-amp (n = 1), CDK4-amp (n = 1), and MYC-amp (n = 1). CONCLUSION: Our study provides real-world clinical evidence from a large cohort that simultaneous inhibition of EGFR and MET could be a more effective therapeutic strategy for patients with MET-amp acquired from EGFR-TKI therapy.

Tumor organoids: synergistic applications, current challenges, and future prospects in cancer therapy.

Patient-derived cancer cells (PDCs) and patient-derived xenografts (PDXs) are often used as tumor models, but have many shortcomings. PDCs not only lack diversity in terms of cell type, spatial organization, and microenvironment but also have adverse effects in stem cell cultures, whereas PDX are expensive with a low transplantation success rate and require a long culture time. In recent years, advances in three-dimensional (3D) organoid culture technology have led to the development of novel physiological systems that model the tissues of origin more precisely than traditional culture methods. Patient-derived cancer organoids bridge the conventional gaps in PDC and PDX models and closely reflect the pathophysiological features of natural tumorigenesis and metastasis, and have led to new patient-specific drug screening techniques, development of individualized treatment regimens, and discovery of prognostic biomarkers and mechanisms of resistance. Synergistic combinations of cancer organoids with other technologies, for example, organ-on-a-chip, 3D bio-printing, and CRISPR-Cas9-mediated homology-independent organoid transgenesis, and with treatments, such as immunotherapy, have been useful in overcoming their limitations and led to the development of more suitable model systems that recapitulate the complex stroma of cancer, inter-organ and intra-organ communications, and potentially multiorgan metastasis. In this review, we discuss various methods for the creation of organ-specific cancer organoids and summarize organ-specific advances and applications, synergistic technologies, and treatments as well as current limitations and future prospects for cancer organoids. Further advances will bring this novel 3D organoid culture technique closer to clinical practice in the future.

Small extracellular vesicles from menstrual blood-derived mesenchymal stem cells (MenSCs) as a novel therapeutic impetus in regenerative medicine.

Menstrual blood-derived mesenchymal stem cells (MenSCs) have great potential in regenerative medicine. MenSC has received increasing attention owing to its impressive therapeutic effects in both preclinical and clinical trials. However, the study of MenSC-derived small extracellular vesicles (EVs) is still in its initial stages, in contrast to some common MSC sources (e.g., bone marrow, umbilical cord, and adipose tissue). We describe the basic characteristics and biological functions of MenSC-derived small EVs. We also demonstrate the therapeutic potential of small EVs in fulminant hepatic failure, myocardial infarction, pulmonary fibrosis, prostate cancer, cutaneous wound, type-1 diabetes mellitus, aged fertility, and potential diseases. Subsequently, novel hotspots with respect to MenSC EV-based therapy are proposed to overcome current challenges. While complexities regarding the therapeutic potential of MenSC EVs continue to be unraveled, advances are rapidly emerging in both basic science and clinical medicine. MenSC EV-based treatment has great potential for treating a series of diseases as a novel therapeutic strategy in regenerative medicine.

Prognosis and Concurrent Genomic Alterations in Patients With Advanced NSCLC Harboring MET Amplification or MET Exon 14 Skipping Mutation Treated With MET Inhibitor: A Retrospective Study.

BACKGROUND: MET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated. METHODS: We retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29). RESULTS: Among evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%). CONCLUSION: MET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification.

Case Report: Transformation From Non-Small Cell Lung Cancer to Small Cell Lung Cancer During Anti-PD-1 Therapy: A Report of Two Cases.

BACKGROUND: Histological transformation of lung cancer to small cell lung cancer (SCLC) is uncommon. It is a small subset of the possible resistance mechanisms, even in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Reports on programmed cell death-1 (PD-1) inhibitors are rare. We report two cases of lung squamous carcinomas that transformed to SCLC during anti-PD-1 therapy, and present a detailed description of histological examination of the pre-and post-transformation tissues, hitherto absent from reports on the topic. CASE PRESENTATION: Case 1: A 69-year-old man was diagnosed with stage IVa squamous cell carcinoma of the lung. He had a programmed cell death-ligand 1 tumor proportion score ≥50%. He achieved partial response after four cycles of sintilimab as first-line treatment. However, sintilimab was discontinued because of severe decrease in hemoglobin levels and platelet counts. Moreover, the occurrence of pleural effusion favored disease progression. Interestingly, bone marrow puncture and biopsy showed transformation to SCLC. Case 2: A 71-year-old man diagnosed with stage IIIa lung squamous cell carcinoma received neoadjuvant chemotherapy, underwent radical surgery, and finally received adjuvant chemotherapy. Five months later, he presented with tumor recurrence. He was treated with nivolumab, though disease progression was observed after four cycles. Notably, a subsequent computed tomography-guided biopsy showed SCLC. CONCLUSION: Phenotypic transformation to SCLC is a potential mechanism of resistance to immunotherapy in squamous cell carcinomas of the lung. Disease progression should prompt re-biopsy to diagnose potential histological changes to assess the requirement for change in treatment.

Two generation reproduction toxicity study of GmDREB3 gene modified wheat in Wistar rats.

To study reproductive toxicity of gene modified wheat generated by introducing DREB3 (drought response element binding protein 3) gene, Wistar rats of were allocated into 3 groups and fed with DREB3 gene modified wheat mixture diet (GM group), non-gene modified wheat mixture diet (Non-GM group) and AIN-93 diet (Control group) from parental generation (F0) to the second offspring (F2). GM wheat and Non-GM wheat, Jimai22, were both formulated into diets at a ratio of 69.55% according to AIN93 diet for rodent animals. Compared with non-GM group, no biologically related differences were observed in GM group rats with respect to reproductive performance such as fertility rate, gestation rate, mean duration, hormone level, reproductive organ pathology and developmental parameters such as body weight, body length, food consumption, neuropathy, behavior, immunotoxicity, hematology and serum chemistry. In conclusion, no adverse effect were found relevant to GM wheat in the two generation reproduction toxicity study, indicating the GM wheat is a safe alternative for its counterpart wheat regarding to reproduction toxicity.