Subsequent Resistance Research Articles

Early continuous glucose monitoring-derived glycemic patterns are associated with subsequent insulin resistance and gestational diabetes mellitus development during pregnancy

BackgroundGestational diabetes mellitus (GDM) and insulin resistance (IR) increase the risk of adverse pregnancy outcomes. We aimed to examine the relationship of interstitial glucose assessed by continuous glucose monitoring (CGM) at early gestation, and the subsequent development of IR and GDM, and to determine 24-h interstitial glucose centile distributions in women with normal (non-IR and non-GDM) and suboptimal glycemic status (IR and/or GDM).MethodsCGM measurements were taken for 3–10 days at 18–24 weeks’ gestation, followed by fasting serum insulin and oral glucose tolerance testing at 24–28 weeks’ gestation. IR and GDM were determined by the updated Homeostasis Model Assessment of IR score of ≥ 1.22 and 2013 World Health Organization criteria, respectively. Risks of IR and GDM were estimated using modified Poisson models, and hourly interstitial glucose centiles determined using Generalized Additive Models for Location, Scale and Shape.ResultsThis prospective cohort study involved 167 pregnant women in Singapore, with a mean age of 31.7 years, body mass index of 22.9 kg/m2, and gestation of 20.3 weeks. 25% of women exhibited IR and 18% developed GDM. After confounders adjustment, women with suboptimal glycemic control, indicated by higher mean daily glucose (risk ratio 1.42; 95% confidence interval 1.16, 1.73), glucose management indicator (1.08; 1.03, 1.12), and J-index (1.04; 1.02, 1.06), as well as those with greater glycemic variability, indicated by higher standard deviation (1.69; 1.37, 2.09), coefficient of variation (1.03; 1.00, 1.06), and mean amplitude of glycemic excursions (1.4; 1.14, 1.35) derived from CGM in early gestation were associated with higher risks of developing IR in later gestation. These associations were similarly observed for the development of GDM. Centile curves showed that, compared to those with normal glycemic status, women with suboptimal glycemic status had higher glucose levels, with greater fluctuations throughout 24 h.ConclusionsIn pregnant women who subsequently developed IR and GDM, interstitial glucose levels assessed by CGM were elevated and varied greatly. This supports the potential use of CGM to screen for glycemic changes early in pregnancy.

Arbuscular mycorrhizal fungi influence belowground interactions between a specialist root-feeder and its natural enemy

As primary producers, plants play a central role in mediating interactions across trophic levels. Although plants are the primary food source for herbivorous insects, they can protect themselves from herbivore damage. Many plants produce toxic compounds that directly reduce herbivore feeding, but plants also protect themselves indirectly by attracting natural enemies of the attacking herbivore through volatile signaling. These so-called tri-trophic interactions have historically been documented aboveground in aerial plant parts but are also known to occur belowground in root systems. In addition to herbivores, plants directly interact with other organisms, which can influence the outcomes of tri-trophic interactions. Arbuscular mycorrhizal fungi (AMF) are symbiotic soil microbes that colonize the roots of plants and facilitate nutrient uptake. These microbes can alter plant chemistry and subsequent resistance to herbivores. Few studies, however, have shown how AMF affect tri-trophic interactions above- or belowground. This study examines how AMF colonization affects the emission of root volatiles when plants are under attack by western corn rootworm, a problematic pest of corn, and subsequent attraction of entomopathogenic nematodes, a natural enemy of western corn rootworm. Mycorrhizal fungi increased rootworm survival but decreased larval weight. Differences were detected across root volatile profiles, but there was not a clear link between volatile signaling and nematode behavior. Nematodes were more attracted to non-mycorrhizal plants without rootworms and AMF alone in soil, suggesting that AMF may interfere with cues that are used in combination with volatiles which nematodes use to locate prey.

Acknowledging Guilt as a First Step Toward Mourning: A Kleinian Response to “Is Healing Possible in Such Context?”

ABSTRACT In this discussion of Ruganci et al (this issue), the author focuses a Kleinian lens on the individual’s resistance to mourning, and highlights the role played by unconscious phantasies and the defenses of splitting and projective identification in the traumatic process. The author details how in trauma, as in normal development, these defenses are called forth by the psyche to manage the inability to tolerate guilt and subsequent resistance to acknowledging destructiveness. This in turn interferes with the capacity to grieve internal object losses triggered by external traumatic events later in life. The author contrasts this understanding of trauma and mourning with the target paper’s depiction of the role of twinship in both.

Concomitant gut dysbiosis and defective gut barrier serve as the bridges between hypercortisolism and chronic systemic inflammation in Cushing's disease.

The aim of this study was to investigate the gut microbial signatures and related pathophysiological implications in patients with Cushing's disease (CD). Twenty-seven patients with CD and 45 healthy controls were enrolled. Based on obtained metagenomics data, we performed correlation, network study, and genome interaction group (GIG) analysis. Fecal metabolomics and serum enzyme linked immunosorbent assay (ELISA) analysis were conducted in dichotomized CD patients. Caco-2 cells were incubated with gradient concentrations of cortisol for subsequent transepithelial electrical resistance (TEER) measurement, FITC-dextran transwell permeability assay, qPCR, and western blot analysis. Gut microbial composition in patients with CD was notably different from that in healthy controls. Network analysis revealed that Eubacterium siraeum might serve as the core specie in the gut microbial system of CD patients. Subsequent GIG analysis identified the positive correlations between GIG9 and UFC. Further serum ELISA and fecal metabolomics uncovered that CD patients with elevated UFC levels were characterized with increased lipopolysaccharide binding protein (LBP). Moreover, remarkable positive association was found between LBP level and relative abundance of E. siraeum. TEER and FITC-dextran transwell assays demonstrated that hypercortisolism induced increased gut permeability. Further qPCR and western blot analysis suggested that dysregulated AhR/Claudin 2 axis might be involved in the development of hypercortisolism-induced defective gut barrier function. Disease activity associated dysbiosis and defective gut barrier might jointly facilitate the development of systemic inflammation in patients with CD.

12233 Weight Gain Following Thyroidectomy For Benign Conditions

Abstract Disclosure: A. Krueger: None. A. Chiu: None. S. Pabich: None. S. Syed: None. A. Poloju: None. S. Holoubek: None. Background: Weight gain is a common complaint of patients with hypothyroidism irrespective of etiology that causes dissatisfaction and decreased quality. Patients often report thyroidectomy as the precipitating event leading to subsequent weight gain and resistance to weight loss. Reported data on body weight changes following surgery are conflicting and there is limited literature on patients with benign pathologies. The average weight gain in the general population has been reported as 0.5/year. The primary outcome of this study was to determine if patients undergoing thyroidectomy for benign conditions experienced greater than expected weight gain compared to the general population when TSH values were controlled. Secondary outcomes assessed were whether pre-operative disease pathology or antibody status affected weight changes. Methods: A retrospective review was performed on 325 patients undergoing total thyroidectomy for benign conditions from January 2015 to December 2020 using the University of Wisconsin Thyroid Surgery Database. The weight change was determined from the time of surgery to the following intervals: 1-2 years, 2-5 years, and >5 years. Study groups were then compared by pathology and presence of antibodies. Exclusion criteria included age <18 years, thyroid cancer, pregnancy within one-year post-surgery, incomplete weight or TSH data, post-operative gastric-bypass surgery, and patients who were not euthyroid pre- and post-op. Results: Our patient population (n=219) gained a mean of 1.58 kg at the 1-2 year interval. There was no significant difference in weight gain based on pathology or antibody status. At the 2-5 year interval, the average weight gain was 2.05 kg and those with antibodies had significantly higher weight gain. Patients with TPO antibodies (n=34) gained a mean weight of 4.58 kg, and those with TRAB and or TSI antibodies (n=17) gained a mean weight of 4.67 kg. Those with both types of antibodies (n=10) did not have any significant weight gain. Conclusion: Conservatively, the expected weight gain of the general population over 2-5 years is 2.5 kg. Using a logistic regression model, patients with autoimmune thyroid disease had twice the odds of gaining more weight than expected by 2-5 years. The presence of auto-immune thyroid antibodies may serve as a target population for intensive weight management programs following surgery. Presentation: 6/1/2024

12233 Weight Gain Following Thyroidectomy For Benign Conditions

Abstract Disclosure: A. Krueger: None. A. Chiu: None. S. Pabich: None. S. Syed: None. A. Poloju: None. S. Holoubek: None. Background: Weight gain is a common complaint of patients with hypothyroidism irrespective of etiology that causes dissatisfaction and decreased quality. Patients often report thyroidectomy as the precipitating event leading to subsequent weight gain and resistance to weight loss. Reported data on body weight changes following surgery are conflicting and there is limited literature on patients with benign pathologies. The average weight gain in the general population has been reported as 0.5/year. The primary outcome of this study was to determine if patients undergoing thyroidectomy for benign conditions experienced greater than expected weight gain compared to the general population when TSH values were controlled. Secondary outcomes assessed were whether pre-operative disease pathology or antibody status affected weight changes. Methods: A retrospective review was performed on 325 patients undergoing total thyroidectomy for benign conditions from January 2015 to December 2020 using the University of Wisconsin Thyroid Surgery Database. The weight change was determined from the time of surgery to the following intervals: 1-2 years, 2-5 years, and >5 years. Study groups were then compared by pathology and presence of antibodies. Exclusion criteria included age <18 years, thyroid cancer, pregnancy within one-year post-surgery, incomplete weight or TSH data, post-operative gastric-bypass surgery, and patients who were not euthyroid pre- and post-op. Results: Our patient population (n=219) gained a mean of 1.58 kg at the 1-2 year interval. There was no significant difference in weight gain based on pathology or antibody status. At the 2-5 year interval, the average weight gain was 2.05 kg and those with antibodies had significantly higher weight gain. Patients with TPO antibodies (n=34) gained a mean weight of 4.58 kg, and those with TRAB and or TSI antibodies (n=17) gained a mean weight of 4.67 kg. Those with both types of antibodies (n=10) did not have any significant weight gain. Conclusion: Conservatively, the expected weight gain of the general population over 2-5 years is 2.5 kg. Using a logistic regression model, patients with autoimmune thyroid disease had twice the odds of gaining more weight than expected by 2-5 years. The presence of auto-immune thyroid antibodies may serve as a target population for intensive weight management programs following surgery. Presentation: 6/1/2024

Diosgenin Alleviates Obesity-Induced Insulin Resistance by Modulating PI3K/Akt Signaling Pathway in Mice Fed a High-Fat Diet.

Obesity is a global medical issue that can be effectively treated by relieving adipose inflammation and subsequent insulin resistance. Diosgenin (DIOS) has various effects as a steroidal saponin in inflammatory disorders. This study explored the effects and mechanism of DIOS on adipose inflammation and insulin sensitivity, both in silico and in vivo. The high-fat diet-induced obesity model in C57BL/6 mice was divided into five groups: normal chow (NC), high-fat diet (HFD), HFD with atorvastatin 10 mg/kg (AT), HFD with DIOS 100 mg/kg (DIOS 100), and HFD with DIOS 200 mg/kg (DIOS 200). Each group underwent an oral intervention for seven weeks. DIOS significantly suppressed weight gain in the body, liver, and epididymal fat pads. Additionally, it significantly improved fasting glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance test results, and reduced the proportion of total and M1 adipose tissue macrophages. Significant changes were shown in mRNA expression of janus kinase 2 (JAK2), insulin receptor (INRS), insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt), all of which exhibited high binding affinity in the in silico. Safety indices, including aspartate aminotransferase (AST), alanine transaminase (ALT), and creatinine level indicated the preventive effects of DIOS. In conclusion, DIOS improves insulin resistance and obesity-associated inflammation via the PI3K/Akt signaling pathway.

High-load and low-volume warm-up increases performance in a resistance training session

IntroductionA warm-up is recommended prior to performing a resistance training workout. Understanding the dose-response effect of warm-up load intensities can contribute to subsequent workout performance. The aim of this study was to compare different warm-up load intensities on subsequent resistance training volume in a workout. MethodsFifteen men who had at least six months of resistance training experience were evaluated. Three resistance training sessions were performed with warm-up load intensities of 40%, 60%, and 80% of the ten-repetition maximum was applied for 15, 10 and 5 repetitions, respectively. Each session consisted of the bench press, inclined leg press, and wide grip lat pulldown exercises performed for three sets to failure with 2 min rest between sets and exercises. ResultsThe 80% warm-up resulted in significantly greater total training volume (TTV) when compared to the 60% (p = 0.010) and 40% (p = 0.038) conditions. In addition, volume load and repetition performance were greater in the 80% condition versus the 60% condition for the bench press (p = 0.037 and p = 0.015, respectively). For the inclined leg press, the difference was close to significance with a probability value of p = 0.055 when comparing the 80% versus 40% protocols. ConclusionBefore starting a resistance training session, it is recommended that a warm-up for each exercise be performed at 80% of the initial workout load.

Association between respiratory disease pathogens in calves near feedlot arrival with treatment for bovine respiratory disease and subsequent antimicrobial resistance status.

This study assessed the risk of first treatment for bovine respiratory disease (BRD) given detection of nasopharyngeal bacteria (Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni) and corresponding likelihood of antimicrobial susceptibility (C/S) at two time points during the early feeding period. Relationships between C/S results and later treatment for BRD were evaluated at both the calf-level and pen-level. The association between calf-level and pen-level C/S findings during the early feeding period and subsequent C/S results at BRD treatment were also reported. Auction-sourced, recently-weaned beef calves (n = 1,599 steers) were placed in adjacent feedlot pens (8 × 100 calves) in two subsequent years. Deep nasopharyngeal (DNP) swabs were collected from all calves at time of arrival processing (1DOF) and before metaphylaxis administration with either tulathromycin or oxytetracycline, 12 days later (13DOF), and at the time of first treatment for BRD. All samples were tested for C/S. Several pen-level and individual calf-level C/S measures of interest were associated with future treatment for BRD and C/S at the time of treatment. The median DOF for first BRD treatment was 24 days following tulathromycin metaphylaxis and 11 days following oxytetracycline. Overall, sampling at 13DOF resulted in the best fit for more models of subsequent treatment for BRD and C/S results at BRD treatment than for sampling at arrival. In individual calves, recovery of M. haemolytica, P. multocida, or H. somni at 13DOF was associated with subsequent treatment for BRD within 45DOF. Pen-level prevalence of Pasteurellacea bacteria with tetracycline or macrolide resistance at arrival and 13DOF were associated with detection of bacteria with antimicrobial resistance (AMR) at BRD treatment, as were individual calf results at 13DOF. These findings suggest that the bacteria and AMR outcomes recovered from cattle near two weeks on feed can inform the prediction of future BRD risk and concurrent antimicrobial susceptibility results at time of first BRD treatment. Notably, the associations between pen-level C/S results from previous testing and corresponding findings in calves with BRD from the same pen suggested potential testing strategies to inform antimicrobial use protocols for feedlot cattle.

Induced expression of AMOT reverses adriamycin resistance in breast cancer cells.

Adriamycin (ADR) is widely used against breast cancer, but subsequent resistance always occurs. YAP, a downstream protein of angiomotin (AMOT), importantly contributes to ADR resistance, whereas the mechanism is largely unknown. MCF-7 cells and MDA-MB-231 cells were used to establish ADR-resistant cell. Then, mRNA and protein expressions of AMOT and YAP expressions were determined. After AMOT transfection alone or in combination with YAP, the sensitivity of the cells to ADR were evaluated in vitro by examining cell proliferation, apoptosis, and cell cycle, as well as in vivo by examining tumor growth. Additionally, the expressions of proteins in YAP pathway were determined in AMOT-overexpressing cells. In the ADR-resistant cells, the expression of AMOT was decreased while YAP was increased, respectively, and the nucleus localization of YAP was increased at the same time. After AMOT overexpression, these were inhibited, whereas the cell sensitivity to ADR was enhanced. However, the AMOT-induced changes were significantly suppressed by YAP knockdown. The consistent results in vivo showed that AMOT enhanced the inhibition of ADR on tumor growth, and inhibited YAP signaling, evidenced by decreased levels of YAP, CycD1, and p-ERK. Our data revealed that decreased AMOT contributed to ADR resistance in breast cancer cells, which was importantly negatively mediated YAP. These observations provide a potential therapy against breast cancer with ADR resistance.

Superhydrophobic Surfaces Prepared from Columnar Units by Convenient Electrodeposition with Excellent Mechanical Stability Impact and Corrosion Resistance.

Regular array structures prepared by laser processing and three-dimensional printing have promising applications in building stable superhydrophobic structures. However, the size of the materials processed by these two methods is affected by the size of the processing equipment, which prevents the processing of large-size materials. In this paper, a columnar unit consisting of a spherical structure with similar mechanical stability to the array structure is designed and prepared for metal surface protection. A convenient electrodeposition method was used to deposit a layer of columnar micron-sized copper consisting of spheres on the surface of a 6061 aluminum alloy. Subsequently, modified ZrO2 nanoparticles and polytetrafluoroethylene (PTFE) were sprayed on the surface to form a superhydrophobic surface with synergistic columnar units and ZrO2 (CAZ). The structure was tested and found to have excellent mechanical stability, maintaining the superhydrophobic properties of the surface even after 200 abrasion cycles of 1000-grit sandpaper under a 500 g load. Moreover, the vertical deformation of the CAZ sample under normal pressure was increased by a factor of 4 compared to the original substrate. Importantly, in subsequent corrosion resistance tests, the CAZ samples showed a two-order-of-magnitude improvement in self-corrosion current density and impedance modulus at low frequencies compared to the original substrate. This strategy is an effective method for preparing mechanically stable superhydrophobic structures that are low-cost and large enough to provide long-term protection for metal surfaces. It is particularly suitable for surface protection of instruments and automotive chassis armor.

Extended-Infusion β-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections

Current evidence is conflicting for associations of extended-infusion β-lactam (EI-BL) therapy with clinical outcomes. To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI). This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion β-lactam (II-BL; ≤1-hour infusions). Statistical analysis was performed from January to October 2023. EI-BL (ie, ≥3-hour infusion). EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (≥4-fold increase in the minimum inhibitory concentration of the β-lactam used to treat the index GN-BSI). Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively (P = .35). In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.

INTERSECTING MEDICAL AND LEGAL RESPONSIBILITIES IN INDONESIA

The primary objective of this research is to illuminate the evolution of medical responsibility in Indonesia over time. By examining the complex interplay between law and medicine, social transformations, medical advancements, and shifting legal perspectives, this study seeks to enhance understanding of medical responsibility in Indonesia. Utilizing an interdisciplinary approach grounded in the "Social Construction of Technology" (SCOT) theory, the research employs historical analysis to trace the origins of medical responsibility, its evolution, and the impact of various legal frameworks and cultural shifts in medicine. The study integrates qualitative data from legal and medical sources to provide a comprehensive view. Findings reveal that the evolution of medical responsibility in Indonesia is closely tied to the adoption of, and subsequent resistance to, entrenched notions within medical discourse. The research identifies a trend towards greater judicial independence from traditional medical narratives and an increased willingness to scrutinize established medical practices, particularly in the context of technological advancements. By situating these developments within Indonesia's historical and cultural context, this research enriches the understanding of medical liability's progression and ongoing transformation within a dynamic healthcare landscape. It addresses gaps in existing literature and offers a nuanced perspective on the interaction between law and medicine concerning medical liability.

Drug-Coated Central Venous Catheters – A Comprehensive Review of Strategies in the Development to Overcome Biofilm Formation and Related Infections

Central venous catheters (CVCs) are implantable medical instruments regularly used in intense care units for the easy introduction of medical drugs and medicaments, to give fluids intravenously, nutriments, transfusion of blood and also to withdraw blood samples. Bloodstream infections associated with the usage of catheters are the most recurrent, harmful as well as expensive impediment. This is the omnipresent reason for the introduction of bacteria and related infections. Among the various types of medical devices, the rate of infection, morbidity and mortality are higher with the usage of CVCs than any other types of medical instruments. Biofilm developed due to contamination by microorganisms. The biofilm is a bunch of microorganisms accumulated on the surface of CVCs. These biofilms contribute to the proliferation of microbes and increase antimicrobial resistance against antibiotics, affect the host’s immunity and get spread to the various body parts. Numerous approaches have been evolved to overcome the above mentioned issues associated with the usage of CVCs. In the said review, the authors have summarized the usage of CVCs, biofilm formation, development of infection, strategies and innovations in the modification of CVCs aiming to avoid the CRBSI and subsequent resistance to antimicrobial drugs.

Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35% and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of SARS-CoV-2, MERS-CoV and other main proteases. Nirmatrelvir inhibited several of these proteases, whereas ensitrelvir was less broadly active. To simulate nirmatrelvir’s clinical use against MERS-CoV and subsequent resistance development, we applied a safe, surrogate virus-based system. Using the surrogate virus, we previously selected hallmark mutations of SARS-CoV-2-Mpro, such as T21I, M49L, S144A, E166A/K/V and L167F. In the current study, we selected a pool of MERS-CoV-Mpro mutants, characterized the resistance and modelled the steric effect of catalytic site mutants S142G, S142R, S147Y and A171S.

Polydatin, a potential NOX5 agonist, synergistically enhances antitumor activity of cisplatin by stimulating oxidative stress in non‑small cell lung cancer.

Non‑small cell lung cancer (NSCLC) is one of the major causes of cancer‑related death worldwide. Cisplatin is a front‑line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin‑mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription‑quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS‑mediated endoplasmic reticulum stress, and the C‑Jun‑amino‑terminal kinase and p38 mitogen‑activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS‑mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review.

Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.

Preventing New Gram-negative Resistance Through Beta-lactam De-escalation in Hospitalized Patients With Sepsis: A Retrospective Cohort Study.

Whether antibiotic de-escalation reduces the risk of subsequent antibiotic resistance is uncertain. We sought to determine if beta-lactam (BL) antibiotic de-escalation is associated with decreased incidence of new Gram-negative resistance in hospitalized patients with sepsis. In a retrospective cohort study, patients with sepsis who were treated with at least 3 consecutive days of BL antibiotics, the first 2 days of which were with a broad-spectrum BL agent defined as a spectrum score (SS) of ≥7 were enrolled. Patients were grouped into three categories: (1) de-escalation of beta-lactam spectrum score (BLSS), (2) no change in BLSS, or (3) escalation of BLSS. The primary outcome was the isolation of a new drug-resistant Gram-negative bacteria from a clinical culture within 60 days of cohort entry. Fine-Gray proportional hazards regression modeling while accounting for in-hospital death as a competing risk was performed. Six hundred forty-four patients of 7742 (8.3%) patients developed new gram-negative resistance. The mean time to resistance was 23.7 days yielding an incidence rate of 1.85 (95% confidence interval [CI]: 1.71-2.00) per 1000 patient-days. The lowest incidence rate was observed in the de-escalated group 1.42 (95% CI: 1.16-1.68) per 1000 patient-days. Statistically significant reductions in the development of new gram-negative resistance were associated with BL de-escalation compared to no-change (hazards ratio (HR) 0.59 [95% CI: .48-.73]). De-escalation was associated with a decreased risk of new resistance development compared to no change. This represents the largest study to date showing the utility of de-escalation in the prevention of antimicrobial resistance.

Function of MYB8 in larch under PEG simulated drought stress

Larch, a prominent afforestation, and timber species in northeastern China, faces growth limitations due to drought. To further investigate the mechanism of larch’s drought resistance, we conducted full-length sequencing on embryonic callus subjected to PEG-simulated drought stress. The sequencing results revealed that the differentially expressed genes (DEGs) primarily played roles in cellular activities and cell components, with molecular functions such as binding, catalytic activity, and transport activity. Furthermore, the DEGs showed significant enrichment in pathways related to protein processing, starch and sucrose metabolism, benzose-glucuronic acid interconversion, phenylpropyl biology, flavonoid biosynthesis, as well as nitrogen metabolism and alanine, aspartic acid, and glutamic acid metabolism. Consequently, the transcription factor T_transcript_77027, which is involved in multiple pathways, was selected as a candidate gene for subsequent drought stress resistance tests. Under PEG-simulated drought stress, the LoMYB8 gene was induced and showed significantly upregulated expression compared to the control. Physiological indices demonstrated an improved drought resistance in the transgenic plants. After 48 h of PEG stress, the transcriptome sequencing results of the transiently transformed LoMYB8 plants and control plants exhibited that genes were significantly enriched in biological process, cellular component and molecular function. Function analyses indicated for the enrichment of multiple KEGG pathways, including energy synthesis, metabolic pathways, antioxidant pathways, and other relevant processes. The pathways annotated by the differential metabolites mainly encompassed signal transduction, carbohydrate metabolism, amino acid metabolism, and flavonoid metabolism.

Ballistic performance of UHMWPE fiber laminates with pre-formed holes

Understanding how previous ballistic impacts affect the subsequent penetration resistance of ultra-high molecular weight polyethylene (UHMWPE) fiber laminates is crucial for their application in multi-hit scenarios. In order to investigate the effect of fiber fracture, a systematic examination of the ballistic performance of UHMWPE laminates with pre-formed holes is conducted through a combined experimental and numerical approach. Penetration resistance, dynamic penetration process, and deformation/failure modes of laminates with different configurations of pre-formed holes are tested and compared. A full three-dimensional finite element model is established, and a continuum homogenized model is utilized to simulate the laminate. The effectiveness of numerical model is validated by achieving a reasonable agreement between predictions and measurements. The presence of a single pre-formed hole will change the severity of delamination and result in tear failures, while it has minimal effect on penetration resistance until the spacing distance reaches 10 mm. When spacing distance remains the same, the change in orientation of a single pre-formed hole has little influence on the velocity history. Further, an enhancement in ballistic performance is observed when the number of pre-formed holes is increased to four, due mainly to the significant pull-in at the edge of pre-formed hole and the released fiber tensile stresses. The results of this study are valuable for comprehending the ballistic performance of UHMWPE laminate when subjected to multiple projectile impacts and have practical implications for the design of advanced protective systems.