Time to next treatment in patients with chronic lymphocytic leukemia initiating first-line ibrutinib or acalabrutinib.

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.

[A case of neonatal liver failure]. / 新生儿肝衰竭1例.

The patient was a male infant, born full-term, admitted to the hospital at 28 days of age due to jaundice for 20 days and abdominal distension for 15 days. The patient developed symptoms of jaundice, hepatosplenomegaly, massive ascites, and progressively worsening liver function leading to liver failure, severe coagulation disorders, and thrombocytopenia one week after birth. Various treatments were administered, including anti-infection therapy, fluid restriction, use of diuretics, use of hepatoprotective and choleretic agents, intermittent paracentesis, blood exchange, and intravenous immunoglobulin, albumin, and plasma transfusions. However, the patient's condition did not improve, and on the 24th day of hospitalization, the family decided to discontinue treatment and provide palliative care. Sequencing of the patient's liver tissue and parental blood samples using whole-exome sequencing did not identify any pathogenic variants that could explain the liver failure. However, postmortem liver tissue pathology suggested congenital hepatic fibrosis (CHF). Given the rarity of CHF causing neonatal liver failure, further studies on the prognosis and pathogenic genes of CHF cases are needed in the future. This article provides a comprehensive description of the differential diagnosis of neonatal liver failure and introduces a multidisciplinary diagnostic and therapeutic approach to neonatal liver failure.

Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: Final results of an open-label, long-term extension study.

Long-chain fatty acid oxidation disorders (LC-FAODs) result in life-threatening energy metabolism deficiencies/energy source depletion. Triheptanoin is an odd-carbon, medium chain triglyceride (that is an anaplerotic substrate of calories and fatty acids) for treating pediatric and adult patients with LC-FAODs. Study CL202 (NCT02214160), an open-label extension study of study CL201 (NCT01886378), evaluated the long-term safety/efficacy of triheptanoin in patients with LC-FAODs (N = 94), including cohorts who were triheptanoin naïve (n = 33) or had received triheptanoin in study CL201 (n = 24) or in investigator-sponsored trials/expanded access programs (IST/EAPs; n = 37). Primary endpoint was the annualized rate of LC-FAOD major clinical events (MCEs; rhabdomyolysis, hypoglycemia, cardiomyopathy). Mean ± standard deviation (SD) triheptanoin treatment durations were 27.4 ± 19.9, 46.9 ± 13.6, and 49.6 ± 21.4 months for the triheptanoin-naïve, CL201 rollover, and IST/EAP cohorts, respectively. In the triheptanoin-naïve cohort, median (interquartile range [IQR]) MCE rate significantly decreased from 2.00 (0.67-3.33) events/patient/year pre-triheptanoin to 0.28 (0.00-1.43) events/patient/year with triheptanoin (p = 0.0343), a reduction of 86%. In the CL201 rollover cohort, mean ± SD MCE rate significantly decreased from 1.76 ± 1.64 events/patient/year pre-triheptanoin to 1.00 ± 1.00 events/patient/year with triheptanoin (p = 0.0347), a reduction of 43%. In the IST/EAP cohort, mean ± SD MCE rate was 1.40 ± 2.37 (median [IQR] 0.57 [0.00-1.67]) events/patient/year with triheptanoin. Safety data were consistent with previous observations. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 68.1% of patients and were mostly mild/moderate in severity. Five patients had seven serious treatment-related TEAEs; all resolved. Our results confirm the long-term efficacy of triheptanoin for patients with LC-FAOD.

PIWIL2 restrains the progression of thyroid cancer via interaction with miR-146a-3p.

OBJECTIVE: The classical role of PIWIL2 is to regulate reproduction by binding to piRNA, but its tumor-related function has received increasing attention in recent years. This study aims to explore its role in the progression of thyroid cancer (TC). METHODS: First, we measured and analyzed the levels of PIWIL2 and miR-146a-3p in TC tissue and adjacent tissues as well as several TC cell lines. We demonstrated the clinical significance of PIWIL2 and miR-146a-3p through the survival rate. Based on these results, we selected TPC-1 and KTC-3 cell lines for our cell experiments. We treated these cell lines with PIWIL2 lentivirus, PIWIL2 siRNA, miR-146a-3p mimic, or miR-146a-3p inhibitor and measured cell proliferation, cell cycle, apoptosis, migration, and invasion. We used PCR and Western blot to quantify the mRNA and protein levels of PIWIL2, while we used luciferase reporter assay and RNA binding protein immunoprecipitation to explore the relationship between miR-146a-3p and PIWIL2. Finally, we developed a xenograft tumor model to confirm the effects of the miR-146a-3p/PIWIL2 axis on TC progression in vivo. RESULTS: We identified that PIWIL2 and miR-146a-3p exhibit opposite expression alterations in TC tissues and that PIWIL2 serves as a 'sponge' by adsorbing miR-146a-3p. Up-regulating PIWIL2 decelerated the proliferation, metastasis, and cell cycle progression of TPC-1 and KTC-3 cells, but accelerated the apoptosis of TC cells, while miR-146a-3p exhibited opposite effects. Finally, overexpressing PIWIL2 restrained the progression of TC in nude mice, which can be reversed by increasing miR-146a-3p expression. Inhibiting PIWIL2, on the other hand, promoted the progression of TC in vivo, which can be reversed by inhibiting miR-146a-3p. CONCLUSION: PIWIL2 may inhibit the progression of TC by sponging miR-146a-3p, providing new insights into the early treatment, recrudescence treatment, and metastasis treatment of TC.

Novel suspension system for gasless transoral vestibular thyroidectomy.

BACKGROUND: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is receiving increased attention, frequently due to growing requirements for cosmetic incisions. Here, we report our initial experience and discuss the safety and efficacy of the innovative surgical working space suspension system for gasless TOETVA. METHODS: We retrospectively analyzed 75 consecutive patients for whom gasless TOETVA with our novel working space suspension system was used. This suspension system included self-developed retractors, a sterile bandage, and an anesthesia stand. We also improved some main surgical instruments in gasless TOETVA. RESULTS: The study included 75 patients who successfully underwent thyroidectomy and central neck dissection via gasless TOETVA. The mean operating time was 143.27 ± 34.60 min. The mean number of retrieved lymph nodes was 8.00 ± 5.39. Conversion to open surgery did not occur, nor did patients exhibit serious postoperative complications. Postoperative complications included 4 cases of transient recurrent laryngeal nerve (RLN) palsy, 9 of transient hypoparathyroidism, and 3 of transient mental nerve injury. One patient with subcutaneous fluid after surgery recovered after aspiration. Another patient with submental minor perforation recovered well after suturing. There was no evidence of specific complications related to self-designed retractors. CONCLUSION: The innovative working space suspension system for gasless TOETVA provided enough and stable working space and optimized the clarity of the surgical field without CO2-related complications.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

All-flesh fruit in tomato is controlled by reduced expression dosage of AFF through a structural variant mutation in the promoter.

The formation of locule gel is an important process in tomato and is a typical characteristic of berry fruit. In this study, we examined a natural tomato mutant that produces all-flesh fruit (AFF) in which the locule tissue remains in a solid state during fruit development. We constructed different genetic populations to fine-map the causal gene for this trait and identified SlMBP3 as the locus conferring the locule gel formation, which we rename as AFF. We determined the causal mutation as a 416-bp deletion in the promoter region of AFF, which reduces its expression dosage. Generally, this sequence is highly conserved among Solanaceae, as well as within the tomato germplasm. Using BC6 near-isogenic lines, we determined that the reduced expression dosage of AFF did not affect the normal development of seeds, whilst producing unique, non-liquefied locule tissue that was distinct from that of normal tomatoes in terms of metabolic components. Combined analysis using mRNA-seq and metabolomics indicated the importance of AFF in locule tissue liquefaction. Our findings provide insights into fruit-type differentiation in Solanaceae crops and also present the basis for future applications of AFF in tomato breeding programs.

Synthesis of Spiro[5.5]trienones- and Spiro[4.5]trienones-Fused Selenocyanates via Electrophilic Selenocyanogen Cyclization and Dearomative Spirocyclization.

A practical strategy for the synthesis of spiro[5.5]trienones-fused selenocyanates and spiro[4.5]trienones-fused selenocyanates through electrophilic selenocyanogen cyclization and dearomative spirocyclization is reported. This approach was conducted under mild conditions with broad substrate scope and good functional group tolerance. The utility of this procedure is exhibited in the late-stage functionalization of nature product and drug molecules.

N-acetylcysteine alleviates ocular surface damage in STZ-induced diabetic mice by inhibiting the ROS/NLRP3/Caspase-1/IL-1ß signaling pathway.

Diabetes mellitus (DM) induces damage to the ocular surface, which leads to vision decline. In the current study, we investigated whether N-acetylcysteine (NAC) plays a protective role in diabetes-induced ocular surface damage. The diabetic mice model was treated with 0.3% NAC topically. Corneal epithelial integrity, tear volume and corneal sensitivity were examined by sodium fluorescein staining, phenol red cotton thread and esthesiometer respectively. The level of reactive oxygen species (ROS) was measured with 2',7-dichlorofluorescein diacetate. The expression of NLRP3, IL-1ß and caspase-1 were evaluated by RT-PCR, western blot and immunostaining. The level of SOD1 was assessed by RT-PCR. We found that the expression of NLRP3, IL-1ß and caspase-1 were elevated in diabetic cornea and conjunctiva. Treatment with NAC improved corneal epithelial integrity, increased tear production and corneal sensitivity in diabetic mice. Moreover, NAC markedly attenuated ROS accumulation and decreased NLRP3, IL-1ß and caspase-1 levels in diabetic cornea and conjunctiva. These results suggest that NAC improves ocular surface damage in STZ-induced diabetic mice, which may be related to the inhibition of the ROS/NLRP3/Caspase-1/IL-1ß signaling pathway.

α-MSH ameliorates corneal surface dysfunction in scopolamine-induced dry eye rats and human corneal epithelial cells via enhancing EGFR expression.

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study.

Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7-carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC-FAOD. CL202 is an open-label, long-term extension study evaluating triheptanoin (Dojolvi) safety and efficacy in patients with LC-FAOD. Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin-naïve (naïve); or had participated in investigator-sponsored trials/expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy-five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other. In the rollover group, mean annualized MCE rate decreased from 1.76 events/year pre-triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre-triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdominal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Triheptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.

Effect of NaOH molarities to the microstructure and sodium storage performance of the Sn-MOF derived SnO2microporous rod.

In this study, we demonstrated a facile method to prepare a novel SnO2microporous rod with various microstructures by controlling NaOH molarities in precursor synthesis processes. Four different molarities of NaOH solution (0.005 M, 0.048 M, 0.12 M and 0.5 M) were used together with o-phthalic acid in Sn-MOF synthesis to determine the effect of ligand [o-C6H4CO222-] concentration on microstructure evolution. It was found that increasing NaOH molarity can effectively decrease the size of Sn-MOF rods. Then, the SnO2microporous rods were obtained by calcinating the as-prepared Sn-MOF as microstructures. Under an optimized experimental condition (NaOH molarity of 0.12 M), the SnO2rods shows a modest initial coulombic efficiency of 61.3% with a high reversible sodium storage capacity of 503 mAh g-1after 150 cycles at 50 mA g-1. Moreover, an impressive reversible sodium storage capacity of 206 mAh g-1can be obtained at long-term cycling performance (800 cycles at current density of 2 A g-1). Effects of morphologies to electrochemical performances have been further discussed in aspects of intrinsic resistance, pseudocapacitive contribution, surface area and porous structure and microstructural stability, and the enhanced electrochemical performance could be attributed to factors of enhanced pseudocapacitive charge contribution, optimized microstructures, and structural stability, which ensure the SnO2-0.12 M to have a good rate performance and cyclability. This nanoscale-engineering method adopted here could be a promising path to fabricate SnO2-based anodes with novel microstructures for sodium storage applications.

Transmission dynamics of SARS-CoV-2 in a mid-size city of China.

BACKGROUND: An outbreak of pneumonia, COVID-19 associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan city and then rapidly spread to other cities. Wenzhou is located approximately 900 km from Wuhan, which was experiencing an outbreak that was severe at the time but is considered modest as the epidemic became a pandemic. We described the epidemiological characteristics of SARS-CoV-2 outside of the epicenter to help understand the transmission pattern in a mid-sized Chinese city. METHODS: To investigate the epidemiological and clinical characteristics of the COVID-19, we described case series of 473 patients with confirmed COVID-19 in Wenzhou, China from January 27 to March 16, 2020. We described the public health interventions of COVID-19 and evaluated the effect of interventions by the effective reproduction number (Rt). RESULTS: The median age of all patients was 47.6 years, 48.4% of whom were female. 33.8% of the patients had a history of residence in Wuhan. Fever (71.7%) and cough (43.1%) were the most common symptoms. In addition, three kinds of unconventional cases were observed, namely 4.9% asymptomatic patients, 7.6% confirmed patients who had no link to Wuhan city but contact with individuals from Wuhan without any symptoms at the time of contact, and 12.9% confirmed patients who had an unknown source of transmission. We estimated that the basic reproductive number (R0) was 2.75 (95% CI: 2.37-3.23). The Rt fluctuated within the range of 2.50 to 3.74 from January 11 to January 16 while gradually reached a peak of 3.74 on January 16. Rt gradually decreased after January 16 and decreased to 1.00 on January 30. Rt continually decreased and reached the lowest point (0.03) on February 21, 2020. CONCLUSION: Our study presented the possibility of asymptomatic carriers affected with SARS-CoV-2, and transmission by these three kinds of unconventional patients in Wenzhou may be an important characteristic of SARS-CoV-2 transmission. The evaluation showed that a series of multifaceted interventions proved effective in controlling the epidemic of COVID-19. These findings might provide valuable examples of control policies for countries or areas in combatting the global pandemic of COVID-19.

Supercollisions of fast H-atom with ethylene on an accurate full-dimensional potential energy surface.

The collisions transferring large portions of energy are often called supercollisions. In the H + C2H2 reactive system, the rovibrationally cold C2H2 molecule can be activated with substantial internal excitations by its collision with a translationally hot H atom. It is interesting to investigate the mechanisms of collisional energy transfer in other important reactions of H with hydrocarbons. Here, an accurate, global, full-dimensional potential energy surface (PES) of H + C2H4 was constructed by the fundamental invariant neural network fitting based on roughly 100 000 UCCSD(T)-F12a/aug-cc-pVTZ data points. Extensive quasi-classical trajectory calculations were carried out on the full-dimensional PES to investigate the energy transfer process in collisions of the translationally hot H atoms with C2H4 in a wide range of collision energies. The computed function of the energy-transfer probability is not a simple exponential decay function but exhibits large magnitudes in the region of a large amount of energy transfer, indicating the signature of supercollisions. The supercollisions among non-complex-forming nonreactive (prompt) trajectories are frustrated complex-forming processes in which the incoming H atom penetrates into C2H4 with a small C-H distance but promptly and directly leaves C2H4. The complex-forming supercollisions, in which either the attacking H atom leaves (complex-forming nonreactive collisions) or one of the original H atoms of C2H4 leaves (complex-forming reactive trajectories), dominate large energy transfer from the translational energy to internal excitation of molecule. The current work sheds valuable light on the energy transfer of this important reaction in the combustion and may motivate related experimental investigations.

Hypermethylation of the OPRM1 and ALDH2 promoter regions in Chinese Han males with alcohol use disorder in Yunnan Province.

BACKGROUND: Alcohol use disorder (AUD) is one of the most serious public health problems worldwide. The OPRM1 and ALDH2 genes are important factors in the reward and alcohol metabolism pathways, and their DNA methylation patterns are closely related to AUD and are population-specific. Chinese Han people are the most populous ethnic group in the world, and this group experiences severe AUD. No epigenetic study on OPRM1 and ALDH2 has been performed in Chinese Han patients with AUD. OBJECTIVES: To investigate whether methylation patterns of OPRM1 and ALDH2 are associated with susceptibility to AUD in Chinese Han males. METHODS: DNA methylation of the OPRM1 and ALDH2 promoters was studied in Chinese Han males with AUD in Yunnan Province (N = 50 controls, N = 90 individuals with AUD) using the bisulfite pyrosequencing method. RESULTS: In the AUD group, compared with the control group, OPRM1 was hypermethylated(p < .01) but there was no significant difference in the methylation level of ALDH2 (p > .05). 9 CpG sites of OPRM1 (p < .05) and 2 CpG sites of ALDH2 (p > .01) were hypermethylated. Smoking promoted AUD-mediated hypermethylation of OPRM1, in which 3 CpG sites showed significant hypermethylation (p < .01). Age had no significant effect on the DNA methylation levels of these two genes. CONCLUSIONS: Our study demonstrates that DNA hypermethylation of the OPRM1 and ALDH2 promoter regions is associated with an increased risk of AUD, which may help to explain the pathogenesis and progression of AUD.

Microarray expression profiling of long noncoding RNAs in the progesterone-treated lung cancer cells.

BACKGROUND: The increasing incidence and unique biological features of lung cancer in women has prompted renewed interest in the role of sex hormones in this disease. We previously showed that progesterone (P4) inhibited lung cancer tumorigenesis and progression. Here, we investigated the effects of P4 on expression of long noncoding RNAs (lncRNAs) and target mRNAs in lung cancer cells. METHODS: We performed high-throughput microarray and bioinformatics analysis to identify differentially expressed lncRNAs and mRNAs in the untreated and the P4-treated A549 human lung cancer cells. RESULTS: In total, 692 lncRNAs and 268 mRNAs were significantly differentially expressed in the P4-treated A549 cells compared to the untreated A549 cells (> 2-fold change, p < 0.05). Of the lncRNAs, 82 and 610 were up-regulated and down-regulated, respectively. Gene ontology, pathway and network analyses showed that many of the mRNAs were involved in the regulation of classical pathways, including Notch signaling. Differential expression of a lncRNA signature composed of NONHSAT000264, FR075921, FR324124, linc-TRIM58, RP1-93H18.7, RP11-120 K9.2, RP11-134F2.2 and NONHSAG024980 was validated by quantitatuve reverse transcriptase-polymerase chain reaction analysis. CONCLUSIONS: This is the first report of differentially expressed lncRNAs in the P4-treated lung cancer cells. The results suggest that lncRNAs could serve as potential therapeutic targets for P4-sensitive lung cancer.

mPRα mediates P4/Org OD02-0 to improve the sensitivity of lung adenocarcinoma to EGFR-TKIs via the EGFR-SRC-ERK1/2 pathway.

The discovery of epidermal growth factor receptor (EGFR) mutations has made EGFR tyrosine kinase inhibitors (EGFR-TKIs) a milestone in the treatment for advanced non-small cell lung cancer (NSCLC). However, patients lacking EGFR mutations are not sensitive to EGFR-TKI treatment and the emergence of secondary resistance poses new challenges for the targeted therapy of lung cancer. In this study, we identified that the expression of membrane progesterone receptor α (mPRα) was associated with EGFR mutations in lung adenocarcinoma patients and subsequently affected the efficacy of EGFR-TKIs. Progesterone (P4) or its derivative Org OD02-0 (Org), which is mediated by mPRα, increases the function of EGFR-TKIs to suppress the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. In addition, the mPRα pathway triggers delayed resistance to EGFR-TKIs. Mechanistic investigations demonstrated that the mPRα pathway can crosstalk with the EGFR pathway by activating nongenomic effects to inhibit the EGFR-SRC-ERK1/2 pathway, thereby promoting antitumorigenic effects. In conclusion, our data describe an essential role for mPRα in improving sensitivity to EGFR-TKIs, thus rationalizing its potential as a therapeutic target for lung adenocarcinomas.

Human umbilical cord mesenchymal stem cells alleviate ongoing autoimmune dacryoadenitis in rabbits via polarizing macrophages into an anti-inflammatory phenotype.

Mesenchymal stem cells (MSCs) exhibit beneficial effects on autoimmune dacryoadenitis. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on rabbit autoimmune dacryoadenitis, an animal model of Sjögren's syndrome (SS) dry eye, and explored whether the effects of MSCs were related to their modulation on macrophage polarization. We have showed that systemic infusion of hUC-MSCs after disease onset efficiently diminished the chronic inflammation in diseased LGs and improved the clinical symptoms. Further analysis revealed that hUC-MSC treatment significantly inhibited the expression of pro-inflammatory M1 macrophage markers iNOS, TNF-α and IL-6, and promoted the expression of anti-inflammatory M2 macrophage markers Arg1, CD206, IL-10, IL-4 and TGF-ß in LGs. Mechanistically, hUC-MSCs activated AKT pathway in macrophages, resulting in upregulation of M2-associated molecule Arg1, which was partly abolished by PI3K inhibitor, LY294002. Together, our data indicated that hUC-MSCs can skew macrophages into an M2 phenotype via affecting AKT pathway. These data may provide a new insight into the mechanisms of hUC-MSCs in the therapy of SS dry eye.

Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway.

Myocardial fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Spermine (SPM), a product of polyamine metabolism, plays an important role in many cardiac diseases including hypertrophy, ischemia, and infarction, but its role in diabetic myocardial fibrosis has not been clarified. This study aimed to investigate the role of polyamine metabolism, specifically SPM, in diabetic myocardial fibrosis and to explore the related mechanisms. We used intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) in Wistar rats and high glucose (HG, 40 mM) stimulated cardiac fibroblasts (CFs) to established a type 1 diabetes (T1D) model in vivo and in vitro, which were pretreated with exogenous SPM (5 mg/kg per day and 5 µM). The results showed that hyperglycemia induced the expression of the key polyamine synthesis enzyme ornithine decarboxylase (ODC) decreased and the key catabolic enzyme spermidine/spermine N1 -acetyltransferase (SSAT) increased compared with those in the control group. The body weight, blood insulin level, and cardiac ejection function were decreased, while blood glucose, heart weight, the ratio of heart weight to body weight, myocardial interstitial collagen deposition, and endoplasmic reticulum stress (ERS)-related protein (glucose-regulated protein-78, glucose-regulated protein-94, activating transcription factor-4, and C/EBP homology protein) expression in the T1D group were all significantly increased. HG also caused an increased expression of Wnt3, ß-catenin (in cytoplasm and nucleus), while Axin2 and phosphorylated ß-catenin decreased. Exogenous SPM improved the above changes caused by polyamine metabolic disorders. In conclusion, polyamine metabolism disorder occurs in the myocardial tissue of diabetic rats, causing myocardial fibrosis and ERS. Exogenous SPM plays a myocardial protective role via inhibiting of ERS and the canonical Wnt/ß-catenin signaling pathway.

COVID-19: asymptomatic carrier transmission is an underestimated problem.

At the present time, COVID-19 is spreading rapidly [1]. The global prevention and control of COVID-19 is focused on the estimation of the relevant incubation period, basic reproduction number (R0), effective reproduction number (Rt) and death risk. Although the prevention and control of COVID-19 requires a reliable estimation of the relevant incubation period, R0, Rt and death risk. Another key epidemiological parameter-asymptomatic ratio that provides strength and range for social alienation strategies of COVID-19, which is widely defined as the proportion of asymptomatic infections among all disease infections. In fact, the ratio of asymptomatic infection is a useful indicator of the burden of disease and a better measurement of the transmissibility of the virus. So far, people have not paid enough attention to asymptomatic carriers. The asymptomatic carriers discussed in this study are recessive infections, that is, those who have never shown symptoms after onset of infection. We will discuss three aspects: detection, infectivity and proportion of healthy carriers.