Trichoplusia ni Transcriptomic Responses to the Phytosaponin Aglycone Hederagenin: Sex-Related Differences.

Many plant species, particularly legumes, protect themselves with saponins. Previously, a correlation was observed between levels of oleanolic acid-derived saponins, such as hederagenin-derived compounds, in the legume Medicago truncatula and caterpillar deterrence. Using concentrations that reflect the foliar levels of hederagenin-type saponins, the sapogenin hederagenin was not toxic to 4th instar caterpillars of the cabbage looper Trichoplusia ni nor did it act as a feeding deterrent. Female caterpillars consumed more diet than males, presumably to obtain the additional nutrients required for oogenesis, and are, thus, exposed to higher hederagenin levels. When fed the hederagenin diet, male caterpillars expressed genes encoding trypsin-like proteins (LOC113500509, LOC113501951, LOC113501953, LOC113501966, LOC113501965, LOC113499659, LOC113501950, LOC113501948, LOC113501957, LOC113501962, LOC113497819, LOC113501946, LOC113503910) as well as stress-responsive (LOC113503484, LOC113505107) proteins and cytochrome P450 6B2-like (LOC113493761) at higher levels than females. In comparison, female caterpillars expressed higher levels of cytochrome P450 6B7-like (LOC113492289). Bioinformatic tools predict that cytochrome P450s could catalyze the oxygenation of hederagenin which would increase the hydrophilicity of the compound. Expression of a Major Facilitator Subfamily (MFS) transporter (LOC113492899) showed a hederagenin dose-dependent increase in gene expression suggesting that this transporter may be involved in sapogenin efflux. These sex-related differences in feeding and detoxification should be taken into consideration in insecticide evaluations to minimize pesticide resistance.

Overcoming resistance to oncolytic virus M1 by targeting PI3K-γ in tumor-associated myeloid cells.

Oncolytic viruses (OVs) have become a category of promising anticancer immunotherapeutic agents over the last decade. However, the fact that many individuals fail to respond to OVs highlights the importance of defining the barely known immunosuppressive mechanisms that lead to treatment resistance. Here we found that the immunosuppression mediated by tumor-associated myeloid cells (TAMCs) directly quenches the antitumor effect of oncolytic virus M1 (OVM). OVM induces myeloid cells to migrate into tumors and strengthens their immunosuppressive phenotypes. Mechanically, tumor cells treated with OVM secrete interleukin-6 (IL-6) to activate the phosphatidylinositol 3-kinase (PI3K)-γ/Akt axis in TAMCs, promoting infiltration of TAMCs and aggravating their inhibition on cytotoxic CD8+ T lymphocytes. Pharmacologically targeting PI3K-γ relieves TAMC-mediated immunosuppression and enhances the efficacy of OVM. Additional treatment with immune checkpoint antibodies eradicates multiple refractory solid tumors and induces potent long-term antitumor immune memory. Our findings indicate that OVM functions as a double-edged sword in antitumor immunity and provide insights into the rationale for liberating T cell-mediated antitumor activity by abolishing TAMC-mediated immunosuppression.

Predictors of bacteremia in febrile infants under 3 months old in the pediatric emergency department.

INTRODUCTION: Fever may serve as the primary indicator of underlying infection in children admitted to the pediatric emergency department (PED), especially in high-risk young infants. This study aimed to identify early clinical factors that could help predict bacteremia in young febrile infants. METHODS: The study included infants under 90 days of age who were admitted to the PED due to fever. Patients were divided into two groups based on the presence or absence of bacteremia and further divided into three age groups: (1) less than 30 days, (2) 30 to 59 days, and (3) 60 to 90 days. Several clinical and laboratory variables were analyzed, and logistic regression and receiver operating characteristic (ROC) analyses were used to identify potential risk factors associated with bacteremia in young febrile infants. RESULTS: A total of 498 febrile infants were included, of whom 6.4% were diagnosed with bacteremia. The bacteremia group had a higher body temperature (BT) at triage, especially in neonates, higher pulse rates at triage, longer fever subsidence time, longer hospital stays, higher neutrophil counts, and higher C-reactive protein (CRP) levels than those of the non-bacteremia group. ROC analysis showed that the best cut-off values for predicting bacteremia in infants with pyrexia were a BT of 38.7 °C, neutrophil count of 57.9%, and CRP concentration of 53.8 mg/L. CONCLUSIONS: A higher BT at triage, increased total neutrophil count, and elevated CRP levels may be useful for identifying bacteremia in young febrile infants admitted to the PED.

Cytotoxic T lymphocyte-associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells.

Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective T-cell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM-1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post-M1 treatment, and its suppressive effect on CD8+ T cells was also elevated. Depletion of Treg cells in M1-treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA-4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45+ immune cells and CD8+ or CD4+ T lymphocytes, decreased ratio of Treg cells to CD4+ T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon-γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1-based oncolytic virotherapy may achieve a highly response in clinical cancer research.

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer.

BACKGROUND: We previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP. METHODS: Microarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. RESULTS: The downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155. CONCLUSIONS: Bmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.

KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.

Oncogenic KRAS plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. However, the mechanism has not been clearly elucidated. RKIP is a tumor repressor, and loss of RKIP has been shown in PDAC. Here, we found that KRAS expression was inversely correlated with RKIP expression in PDAC fresh tissue regardless of the KRAS mutant status. The negative correlation between KRAS and RKIP was further confirmed in our PDAC tissue microarray. KRAS overexpression and RKIP downregulation were associated with poor clinical outcomes. Knockdown or overexpression of KRAS in PDAC cell lines robustly increased or decreased, respectively, RKIP protein and mRNA levels. Furthermore, the MAPK-ERK pathway was involved in the regulation of RKIP. KRAS-regulated RKIP expression, which in turn affected the expression of pivotal epithelial-mesenchymal transition (EMT) and apoptosis factors. The biological function of the KRAS-RKIP axis was demonstrated in human pancreatic cancer cells in vitro and in vivo. KRAS knockdown increased RKIP expression and inhibited metastasis and chemoresistance. Moreover, the feature of metastasis and chemoresistance was rescued in the KRAS-knockdown cells through the inhibition of RKIP by RNA interference. In conclusion, our studies demonstrate how KRAS inhibits the tumor suppressor RKIP, thus offering novel justification for targeting RKIP as a strategy to overcome KRAS-induced tumor metastasis and chemoresistance in PDAC.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) HepaRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6-559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.

Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.

Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.

It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.

BACKGROUND: B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP) are involved in cancer metastasis and chemotherapeutic resistance, respectively. In this study, we evaluated the association between Bmi-1 and RKIP and outcome of gastric cancer through clinical data analysis and in vitro experiments. METHODS: Bmi-1 expression and RKIP expression were observed in 107 cases of gastric cancer through use of tissue microarray technology to identify their correlations with clinicopathological parameters, patient survival, and susceptibility to chemotherapy. The correlation was confirmed in gastric cancer cell lines, analyzed further by gene overexpression and silencing analysis, a cell invasion assay, and a chemosensitivity test. RESULTS: Positive expression of Bmi-1 was highly correlated with T classification and clinical stage. Diminished or lost expression of RKIP was significantly associated with T classification, lymph node metastasis, distant metastasis, and clinical stage. Bmi-1 is negatively and RKIP is positively related to patient survival. Positive expression of Bmi-1 and negative expression of RKIP are associated with poor patient survival and modest efficacy of postoperative chemotherapy. A meaningfully inverse association between Bmi-1 and RKIP was found in tissue microarray studies, and was verified further in gastric cancer cell lines. Moreover, gene overexpression and silencing analysis indicated that RKIP might be regulated by Bmi-1. Furthermore, the impacts of Bmi-1 on cell invasion and chemotherapy resistance were rescued by knockdown of RKIP. CONCLUSIONS: Our study implies that detection of Bmi-1 and RKIP is valuable in predicting patient survival and therapeutic response in gastric cancer, and the inverse association between Bmi-1 and RKIP reveals the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.

Review of Ultrasonography in the Diagnosis of Carpal Tunnel Syndrome and a Proposed Scanning Protocol.

Carpal tunnel syndrome is the most common peripheral compressive neuropathy. Ultrasonography (US) is an emerging technology that can be used in the diagnosis of carpal tunnel syndrome. Although the cross-sectional area is the most studied and validated measurement for carpal tunnel syndrome, there is no standardized neuromuscular US scanning protocol. We review the most studied neuromuscular US characteristics and protocols in the evaluation of carpal tunnel syndrome and propose a standardized protocol for evaluating carpal tunnel syndrome with neuromuscular US based on current literature.

Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer.

The synergetic inhibitory effects on human pancreatic cancer by nanoparticle-mediated siRNA and arsenic therapy were investigated both in vitro and in vivo. Poly(ethylene glycol)-block-poly(L-lysine) were prepared to form siRNA-complexed polyplex and poly(ethylene glycol)-block-poly(DL-lactide) were prepared to form arsenic-encapsulated vesicle, respectively. Down-regulation of the mutant Kras gene by siRNA caused defective abilities of proliferation, clonal formation, migration, and invasion of pancreatic cancer cells, as well as cell cycle arrest at the G0/G1 phase, which substantially enhanced the apoptosis-inducing effect of arsenic administration. Consequently, co-administration of the two nanomedicines encapsulating siRNA or arsenic showed ideal tumor growth inhibition both in vitro and in vivo as a result of synergistic effect of the siRNA-directed Kras oncogene silencing and arsenic-induced cell apoptosis. These results suggest that the combination of mutant Kras gene silencing and arsenic therapy using nanoparticle-mediated delivery strategy is promising for pancreatic cancer treatment. FROM THE CLINICAL EDITOR: Treatment of pancreatic cancer remains a major challenge. These authors demonstrate a method that combines a siRNA-based Kras silencing with arsenic delivery to pancreatic cancer cells using nanoparticles, resulting in enhanced apoptosis induction in the treated cells.

Novel Ultrasound-Guided Radiofrequency Ablation of the Epicondylar Branch of the Posterior Cutaneous Nerve of the Forearm for Recalcitrant Lateral Epicondylosis.

This report describes a novel technique for the treatment of recalcitrant lateral epicondylosis (LE) by radiofrequency ablation (RFA) of the epicondylar branch of the posterior cutaneous nerve of the forearm (PCNF-BrEpi). Here, we describe two patients suffering from recalcitrant LE who were treated with ultrasound-guided RFA of the PCNF-BrEpi in the outpatient pain clinic setting. Patient follow-up was made at eight weeks, five months, and seven months. Numerical pain rating (NPR) for pain and Upper Extremity Functional Index-15 (UEFI-15) were obtained at baseline and at each of the follow-ups. Both patients reported significant improvement in their pain and function quickly. RFA may be a viable treatment option for recalcitrant LE. Larger comparative trials and further investigation are needed to establish results in comparison to conventional treatments and to validate RFA as a treatment option in recalcitrant LE.

Prognostic value of RRM1 and its effect on chemoresistance in pancreatic cancer.

PURPOSE: Pancreatic cancer (PC) remains a lethal disease, and gemcitabine resistance is prevalent. However, the biomarkers suggestive of gemcitabine resistance remain unclear. METHODS: Bioinformatic tools identified ribonucleotide reductase catalytic subunit M1 (RRM1) in gemcitabine-related datasets. A cox regression model revealed the predictive value of RRM1 with clinical features. An external clinical cohort confirmed the prognostic value of RRM1. RRM1 expression was validated in gemcitabine-resistant cells in vitro and in orthotopic PC model. CCK8, flow cytometry, transwell migration, and invasion assays were used to explore the effect of RRM1 on gemcitabine-resistant cells. The CIBERSORT algorithm investigated the impact of RRM1 on immune infiltration. RESULTS: The constructed nomogram based on RRM1 effectively predicted prognosis and was further validated. Moreover, patients with higher RRM1 had shorter overall survival. RRM1 expression was significantly higher in PC tissue and gemcitabine-resistant cells in vitro and in vivo. RRM1 knockdown reversed gemcitabine resistance, inhibited migration and invasion. The infiltration levels of CD4 + T cells, CD8 + T cells, neutrophils, and plasma cells correlated markedly with RRM1 expression, and communication between tumor and immune cells probably depends on NF-κB/mTOR signaling. CONCLUSION: RRM1 may be a potential marker for prognosis and a target marker for gemcitabine resistance in PC.

Effect of sublethal concentrations of the bioinsecticide spinosyn treatment of Trichoplusia ni eggs on the caterpillar and its parasitoid, Trichogramma brassicae.

BACKGROUND: Integrated Pest Management (IPM) seeks to combine multiple management strategies for optimal pest control. One method that is successfully employed in IPM is the use of beneficial organisms. However, in severe circumstances when pest insects exceed threshold limits, insecticides may still need to be implemented. Thus, understanding the effects of insecticides on biocontrol agents, such as parasitoid wasps, is paramount to ensure sustainable agroecosystems. Sublethal effects of the bioinsecticide spinosyn, a mixture of the bacterial Saccharopolyspora spinosa (Mertz and Yao) fermentation products spinosyn A and D, on eggs of Trichoplusia ni (Hübner), a cruciferous crop pest, and its egg parasitoid Trichogramma brassicae (Bezdenko) was investigated. RESULTS: The LC50 for spinosyn A and D (dissolved in ethanol) on T. ni eggs is 54 ng mL-1. Transcriptomics on caterpillars (1st and 3rd instars) that hatched from eggs treated with sublethal concentrations of spinosyn identified the upregulation of several genes encoding proteins that may be involved in insecticide resistance including detoxification enzymes, such as cytochrome P450s, glutathione S-transferases and esterases. Sublethal T. ni egg treatments did not affect parasitoid emergence, however, there was a marked increase in the size of T. brassicae hind tibia and wings that emerged from spinosyn-treated eggs. CONCLUSIONS: For the caterpillar, treatment of eggs with sublethal concentrations of spinosyn may induce insecticide resistance mechanisms. For the parasitoids, their increased size when reared in spinosyn-treated eggs suggests that the emerged wasps may have higher performance. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Long-Term Pulmonary and Neurodevelopmental Outcomes of Meconium Aspiration Syndrome Affected Infants: A Retrospective National Population-Based Study in Taiwan.

INTRODUCTION: Meconium aspiration syndrome (MAS) may cause severe pulmonary and neurologic injuries in affected infants after birth, leading to long-term adverse pulmonary or neurodevelopmental outcomes. METHODS: This retrospective population-based cohort study enrolled 1,554,069 mother-child pairs between 2004 and 2014. A total of 8,049 infants were in the MAS-affected group, whereas 1,546,020 were in the healthy control group. Children were followed up for at least 3 years. According to respiratory support, MAS was classified as mild, moderate, and severe. With the healthy control group as the reference, the associations between MAS severity and adverse pulmonary outcomes (hospital admission, intensive care unit (ICU) admission, length of hospital stay, or invasive ventilator support during admission related to pulmonary problem) or adverse neurodevelopmental outcomes (cerebral palsy, needs for rehabilitation, visual impairment, or hearing impairment) were accessed. RESULTS: MAS-affected infants had a higher risk of hospital and ICU admission and longer length of hospital stay, regardless of severity. Infants with severe MAS had a higher risk of invasive ventilator support during re-admission (odds ratio: 17.50, 95% confidence interval [CI]: 7.70-39.75, p < 0.001). Moderate (hazard ratio [HR]: 1.66, 95% CI: 1.30-2.13, p < 0.001) and severe (HR: 4.94, 95% CI: 4.94-7.11, p < 0.001) MAS groups had a higher risk of adverse neurodevelopmental outcome, and the statistical significance remained remarkable in severe MAS group after adjusting for covariates (adjusted HR: 2.28, 95% CI: 1.54-3.38, p < 0.001) Conclusions: Adverse pulmonary or neurodevelopmental outcomes could occur in MAS-affected infants at birth. Close monitoring and follow-up of MAS-affected infants are warranted.

Novel Ultrasound-Guided Radiofrequency Ablation of the Medial Epicondylar Sensory Nerve for Recalcitrant Medial Epicondylosis: A Case-Based Technical Report.

Recalcitrant medial epicondylosis (ME) is a chronic tendinopathy affecting the common flexor-pronator tendon origin which causes significant pain and functional limitations. Recalcitrant ME is difficult to manage with non-surgical treatment options. The medial epicondylar sensory nerve (MEsn) is a small sensory nerve that travels within the medial intermuscular septum to innervate the osseous-tendinous structures of the medial epicondyle. In this report, we describe a novel technique for the treatment of recalcitrant ME via radiofrequency ablation (RFA) of the MEsn under ultrasound guidance. The MEsn is localized under ultrasound in the medial distal arm, just proximal to the medial epicondyle. Patients with a positive prognostic block of the MEsn subsequently underwent RFA of the MEsn. We have performed this procedure on two patients who have demonstrated improvement in pain and function for up to nearly one year after the procedure. The relief from pain and improvement in function of these patients warrants further investigation and comparative trials with respect to conventional treatment options, as MEsn RFA may be a viable treatment option for recalcitrant ME.

Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis.

Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. And a specific drug that is closely related to the mechanism is urgently required to sensitize GEM. Here, tissue inhibitor of matrix metalloproteinases 1 (TIMP1) and phosphorylated mammalian target of rapamycin (p-mTOR) were found to be substantially elevated in PDAC patients and were associated with worse overall survival. The TIMP1/PI3K/AKT/mTOR pathway was found in GEM-resistant PDAC cells and was revealed to be involved in epithelial-mesenchymal transition (EMT) and apoptosis. Furthermore, arsenic trioxide (ATO), a basic therapeutic drug for acute promyelocytic leukemia, mediated TIMP1 reduction by inducing reactive oxygen species generation and hampered the subsequent PI3K/AKT/mTOR axis. Moreover, the combination of ATO and GEM cooperatively suppressed the TIMP1/PI3K/AKT/mTOR pathway, synergistically inhibited EMT and promoted apoptosis. In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.

Epidemiological evolution of early-onset neonatal sepsis over 12 years: A single center, population-based study in central Taiwan.

BACKGROUND: We aimed to explore the epidemiology and evolution of pathogens, antibiotic susceptibility, and mortality rate in cases of neonatal early-onset sepsis (EOS) reported over a period of 12 years in a level III neonatal center in Central Taiwan. METHODS: Patients' medical records in a neonatal center from 2007 to 2018 were reviewed to obtain information on infants with culture-proven EOS, which included pathogens found in the blood or cerebrospinal fluid cultures. RESULTS: The incidence of neonatal EOS during this period was 2.11 cases/1,000 admissions. Group B streptococcal (GBS) and Escherichia coli were the most common pathogens. The overall rates of GBS and E. coli infections were 0.68/1,000 and 0.77/1,000 live births, respectively. The incidence of EOS in infants with a birth weight ≥1,500 g decreased significantly with decreasing incidence of GBS-related sepsis. The incidence of EOS remained high in very-low-birth-weight (VLBW) infants and increased over time. There was an increasing trend in of E. coli infection and emergence of drug-resistant strains. In addition, E. coli sepsis had high mortality in VLBW infants. CONCLUSION: Novel screening and prevention strategies against E. coli and reserving broad-spectrum antibiotics for the most critically ill or VLBW patients with maternal chorioamnionitis might help in early diagnosis and further improve the outcomes of EOS.