Medium Chain Length Polyhydroxyalkanoate Production by Engineered Pseudomonas gessardii Using Acetate-formate as Carbon Sources.

Production of medium chain length polyhydroxyalkanoate (mcl-PHA) was attempted using Pseudomonas gessardii NIBRBAC000509957, which was isolated from Sunchang, Jeollabuk-do, Republic of Korea (35°24'27.7"N, 127°09'13.0"E) and effectively utilized acetate and formate as carbon sources. We first evaluated the utilization of acetate as a carbon source, revealing optimal growth at 5 g/L acetate. Then, formate was supplied to the acetate minimal medium as a carbon source to enhance cell growth. After overexpressing the acetate and formate assimilation pathway enzymes, this strain grew at a significantly higher rate in the medium. As this strain naturally produces PHA, it was further engineered metabolically to enhance mcl-PHA production. The engineered strain produced 0.40 g/L of mcl-PHA with a biomass content of 30.43% in fed-batch fermentation. Overall, this strain can be further developed to convert acetate and formate into valuable products.

Clinical results of arthroscopically-assisted lower trapezius transfer using fascia lata autograft for posterior superior irreparable rotator cuff tear.

Background: Different interpositional grafts have been proposed to connect between the lower trapezius tendon (LTT) to the humerus during LTT transfer. While studies often mention the successful use of Achilles tendon allograft, there is currently no literature reporting the clinical outcomes of utilizing fascia lata autograft (FLA) in LTT transfer. Therefore, the current study aims to evaluate the clinical and radiologic results of LTT using FLA for posterior superior irreparable rotator cuff tears (PSIRCTs) without arthritis. Patient and methods: The present study constitutes a retrospective case series involving 22 patients, with a mean follow-up of 35.9 ± 15.9 months. Pain levels were gauged using the Visual Analog Scale (VAS), while shoulder function was comprehensively assessed through the Constant and ASES (American Shoulder and Elbow Society) scores. The evaluation of shoulder activities in daily living employed the ADLER (Activities of Daily Living Requiring Active External Rotation) score. Active ROM (Range of Motion) of all directions were obtained, radiologic assessments included key parameters such as AHD (Acromion Humeral Distance) and the Hamada grade. Finally, the integrity of the transferred LTT was evaluated, and a subgroup analysis was undertaken based on Tm trophicity. Results: By the final follow-up period, VAS, Constant, ASES, and ALDER demonstrated significant improvement. Active ROM significantly improved in (FE) forward elevation to 155° ± 29°, abduction (Abd) to 140° ± 32°, external rotation (ER) at 90° Abd to 68° ± 19°, and ER at the side to 39° ± 17°. AHD and Hamada grade showed no significant arthritic progression. Tm hypertrophy group experienced superior improvements in ER compared to that of the non-hypertrophy group. Complications included re-tear (n = 2), infection (n = 1) and donor-site morbidity (n = 1). Conclusion: The study highlighted promising clinical outcomes of LTT transfer using FLA, with no significant complications. Along with Achilles tendon allograft, FLA can be a safe and viable alternative interpositional graft choice.

Mid-term Outcome of Superior Capsular Reconstruction Using Fascia Lata Autograft (At Least 6 mm in Thickness) Results in High Retear Rate and No Improvement in Muscle Strength.

PURPOSE: (1) To report and evaluate clinical and radiologic outcomes of superior capsular reconstruction (SCR) using fascia lata autograft in patients with irreparable rotator cuff tears (IRCTs) over a mid-term duration and (2) to assess the overall survival rate of the graft. METHODS: We retrospectively reviewed patients who underwent SCR with fascia lata autograft between June 2017 and August 2018. The graft, folded 3 or 4 times, achieved a minimum thickness of 6 mm during the surgical procedure. The inclusion criteria encompassed patients with isolated supraspinatus IRCTs or posterosuperior IRCTs exhibiting poor muscle quality (Goutallier grade ≥3) and without arthritis (Hamada grade ≤ 2). The exclusion criteria included lack of follow-up data or magnetic resonance imaging. Clinical assessments included the visual analog scale score, Constant score, and American Shoulder and Elbow Surgeons (ASES) score; active range of motion; and strength. Radiographic analysis included the acromiohumeral distance, Hamada grade, and graft integrity at final follow-up. A Kaplan-Meier curve was generated to depict SCR graft survivorship. RESULTS: In total, 45 patients (mean age, 64.8 ± 5.7 years) were included, and the average follow-up duration was 63.2 ± 5.9 months (range, 50-79 months). There was significant improvement in pain (visual analog scale score of 4.4 ± 1.3 preoperatively vs 1.4 ± 0.4 at final follow-up, P < .001). Yet, 18 patients (40.0%) and 17 patients (37.7%) achieved the minimal clinically important difference in the ASES score and Constant score, respectively. Active forward elevation increased from 119° ± 23° to 137° ± 23° (P < .001), and external rotation at the side improved from 29° ± 11° to 36° ± 12° (P = .002). However, strength did not exhibit improvement in any direction. The acromiohumeral distance decreased from 8.5 ± 1.7 mm to 6.5 ± 1.9 mm (P < .001), and the Hamada grade increased from 1.1 ± 0.3 to 1.8 ± 1.1 (P < .001). Finally, the infection rate was 13.3% (n = 6). CONCLUSIONS: Despite a substantial graft retear rate of 62.2%, SCR led to a significant improvement in pain. Nonetheless, 18 patients (40.0%) and 17 patients (37.7%) achieved the minimal clinically important difference in the ASES score and Constant score, respectively. Forward elevation and external rotation at the side showed significant improvement, but no improvement in muscle strength was observed. Finally, significant arthritis progression was observed. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Increased latissimus dorsi and teres major muscle volume after anterior transfer for irreparable anterior superior rotator cuff tear: correlation with improved internal rotation strength.

INTRODUCTION: While the well-established correlation between increased muscle volume and enhanced muscle strength is widely recognized, there have been no studies assessing volumetric muscle changes in transfer surgery in the shoulder. This study aimed to evaluate changes in transferred muscle volume and their clinical implications in anterior latissimus dorsi and teres major (aLDTM) tendon transfer in patients with anterior superior irreparable rotator cuff tears (ASIRCTs). MATERIALS AND METHODS: The study retrospectively examined 40 patients who underwent aLDTM tendon transfers for ASIRCTs between August 2018 and January 2022. Using ImageJ software, the LDTM muscle was segmented in T2-weighted oblique axial images, and total muscle volume (tLDTMV) of both immediate and postoperative 1-year were calculated. Pearson correlation analysis was used to determine the correlation between ΔtLDTMV and ΔASES scores, Δactive-ROM, and Δstrength. RESULTS: The current study revealed an 11.4% increase in tLDTMV at 1-year postoperative. Patients were grouped based on postoperative ASES score: Group 1 (Optimal, n = 17) and Group 2 (Suboptimal, n = 23). Although tLDTMVimmediate postoperative values were similar between groups (P = 0.954), tLDTMV1-year postoperative value was significantly higher in Group 1 compared to Group 2 (P = 0.021). In correlation analysis, ΔtLDTMV showed significant correlations with ΔASES score (r = 0.525, P < 0.001), ΔaROM of forward elevation (FE) (r = 0.476, P = 0.002), ΔaROM of internal rotation (IR) at back (r = 0.398, P = 0.011), Δstrength of FE (r = 0.328, P = 0.039), Δ strength of IR at 90° abduction (r = 0.331, P = 0.037), and IR at side (r = 0.346, P = 0.029). CONCLUSIONS: Significant increase in tLDTMV was observed at 1-year postoperative for ASIRCT patients. Notably, greater ΔtLDTMV exhibited a correlation with better ASES scores, increased aROM and strength in both FE and IR. Nevertheless, further research is required by employing more robust standardized measurement tools and a larger sample size.

Joint-preserving treatment for global irreparable rotator cuff tears: combined anterior Latissimus dorsi and Teres major tendon transfer.

INTRODUCTION: Treating global irreparable rotator cuff tears (GIRCTs) that involve both antero-and postero-superior cuff tendon tears could be a challenging problem. There has been limited joint-preserving treatment options in high-demand patients with minimal glenohumeral arthritis. The study aims to assess the clinical outcome of combined anterior latissimus dorsi and teres major tendon (aLDTM) transfer for patients with both GIRCTs and minimal glenohumeral arthritis. MATERIALS AND METHODS: This retrospective study included patients who underwent combined aLDTM transfer for GIRCTs between 2018 May and 2020 October. Clinical outcomes include pain VAS, Constant, American Shoulder and Elbow Society (ASES), University of California Los Angeles (UCLA), activities of daily living requiring active internal rotation (ADLIR) score, active range of motion (aROM), strength, rates of pseudoparalysis or pseudoparesis reversal and return to work. Radiographic assessment included the acromiohumeral distance (AHD), Hamada grade, and transferred tendon integrity at final follow-up. RESULTS: 23 patients (mean age: 64.7 ± 5.9 years [55-74]) were included and the mean follow-up period was 28.2 ± 4.3 [24‒36] months. Postoperatively, VAS, Constant, ASES, UCLA, and ADLIR scores significantly improved at final follow-up (P < .001). Postoperative aROM was significantly improved in forward elevation (FE) to 129° ± 29°, abduction (ABD) to 105° ± t3°, and internal rotation (IR) at back to 5.9 ± 2.5. Strength of both FE and IR were also significantly improved (P < .001). Patients with preoperative pseudoparalysis (2 of 4 patients) and pseudoparesis (6 of 6 patients) experienced a reversal. No significant change in AHD and hamada grade was confirmed at final follow-up. 3 patients experienced partial tear of the transferred tendon. CONCLUSIONS: In this study, we found significant improvement in clinical outcomes with no significant progression of arthritis by final follow-up. The aLDTM transfer could be an alternative choice of joint-preserving treatment option for young and active patients with GIRCTs and minimal glenohumeral arthritis. However, large and long-term studies should be conducted to establish its adequacy. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: IV.

Mid-term outcomes of arthroscopically assisted lower trapezius tendon transfer using Achilles allograft in treatment of posterior-superior irreparable rotator cuff tear.

BACKGROUND: Arthroscopically assisted lower trapezius tendon (aLTT) transfer is one of the treatment options for posterior-superior irreparable rotator cuff tears (PSIRCTs). Although short-term clinical outcomes have shown promising results, there are currently no reported clinical outcomes over a longer follow-up period. This study evaluated the mid-term outcomes of aLTT transfer in patients with a diagnosis of PSIRCT. METHODS: This retrospective case-series study included patients who underwent aLTT transfer between May 2017 and May 2019. The clinical outcome assessment included the visual analog scale (VAS) pain score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, Activities of Daily Living Requiring Active External Rotation (ADLER) score, active range of motion, Single Assessment Numeric Evaluation score, and return-to-work rate. The radiographic analysis included the acromiohumeral distance, Hamada grade, and integrity of the transferred tendon at final follow-up. Subgroup analyses were performed based on the integrity of the transferred tendon and the trophicity of the teres minor (Tm). RESULTS: This study enrolled 36 patients with a mean age of 63.4 years who met the inclusion criteria and were followed up for a mean of 58.2 ± 5.3 months. At final follow-up, the patients showed significant improvement in mean VAS score, Constant score, American Shoulder and Elbow Surgeons score, University of California-Los Angeles score, ADLER score, and active range of motion in all directions except internal rotation. A decrease in the acromiohumeral distance and an increase in the Hamada grade were observed at final follow-up (P = .040 and P = .006, respectively). Retears of the transferred tendon occurred in 7 patients, and postoperative infections developed in 2 individuals. An interesting finding was that the retear group still demonstrated improvement in the VAS score but did not show improvement in external rotation at the side by the final follow-up. Compared with the Tm non-hypertrophy group, the Tm hypertrophy group showed significantly better improvement in external rotation at 90° of abduction and at the side, as well as the ADLER score. Of the study patients, 30 (83.3%) were able to successfully resume their previous work. CONCLUSION: In this study, aLTT transfer in patients with PSIRCTs demonstrated significant improvements in clinical and radiologic outcomes by the final follow-up. These findings provide support for the mid-term safety and effectiveness of aLTT transfer as a viable joint-preserving treatment option for PSIRCTs. However, larger and longer-term studies are still needed to further validate these findings.

Overexpression of Interleukin-8 Promotes the Progression of Fatty Liver to Nonalcoholic Steatohepatitis in Mice.

Nonalcoholic steatohepatitis (NASH) is an advanced stage of fatty liver disease characterized by liver damage, inflammation, and fibrosis. Although neutrophil infiltration is consistently observed in the livers of patients with NASH, the precise role of neutrophil-recruiting chemokines and infiltrating neutrophils in NASH pathogenesis remains poorly understood. Here, we aimed to elucidate the role of neutrophil infiltration in the transition from fatty liver to NASH by examining hepatic overexpression of interleukin-8 (IL8), a major chemokine responsible for neutrophil recruitment in humans. Mice fed a high-fat diet (HFD) for 3 months developed fatty liver without concurrent liver damage, inflammation, and fibrosis. Subsequent infection with an adenovirus overexpressing human IL8 for an additional 2 weeks increased IL8 levels, neutrophil infiltration, and liver injury in mice. Mechanistically, IL8-induced liver injury was associated with the upregulation of components of the NADPH oxidase 2 complex, which participate in neutrophil oxidative burst. IL8-driven neutrophil infiltration promoted macrophage aggregate formation and upregulated the expression of chemokines and inflammatory cytokines. Notably, IL8 overexpression amplified factors associated with fibrosis, including collagen deposition and hepatic stellate cell activation, in HFD-fed mice. Collectively, hepatic overexpression of human IL8 promotes neutrophil infiltration and fatty liver progression to NASH in HFD-fed mice.

Prevalence, Trend, and Risk Factors for Early Chronic Obstructive Pulmonary Disease: An Analysis of the Nationwide Population-Based Survey from 2010 to 2019 in South Korea.

This study aimed to evaluate the prevalence, trends, and risk factors of early chronic obstructive pulmonary disease (COPD) by using a nationally representative sample. The datasets of the Korea National Health and Nutrition Examination Survey 2010-2019 were used, where 80,860 individuals were identified; of these, 9,045 participants aged 40-49 years who underwent spirometry with no missing data were analyzed. Early COPD was defined as forced expiratory volume in 1 s /forced vital capacity ratio < the lower limit of normal (2.5th percentile) in individuals aged <50 years without a history of asthma, inhaler therapy, or persistent respiratory symptoms. The prevalence and trend of early COPD were estimated according to features such as smoking status and pack-years. Joinpoint regression analysis was used to analyze the significant annual change in the trend according to sex, smoking status, and pack-years. A complex sample multivariable-adjusted regression model was used to identify factors affecting early COPD. The estimated population size during 2010-2019 was 82,326,178. Early COPD was present in 4.5% of patients (6.5% of men and 2.3% of women). It was present in 7.7% of current smokers, followed by former and never smokers. Among smokers with ≥ 10 pack-years, early COPD was present in 8.2%, whereas it was present in 2.6% of smokers with < 10 pack-years. Joinpoint regression analyses found a recent decrease in the trend of prevalence in males who were former and current smokers. The multivariable-adjusted logistic regression model showed that being male, lower educational level, smoking status, and pack-years were factors that affected the presence of early COPD. Continued surveillance of this pre-disease condition is required, and further research are warrant.

Protective effects of isoflavones on alcoholic liver diseases: Computational approaches to investigate the inhibition of ALDH2 with isoflavone analogues.

Excessive and chronic alcohol intake can lead to the progression of alcoholic liver disease (ALD), which is a major cause of morbidity and mortality worldwide. ALD encompasses a pathophysiological spectrum such as simple steatosis, alcoholic steatohepatitis (ASH), fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC). Aldehyde dehydrogenase (ALDH2) is the most vital enzyme that produces acetate from acetaldehyde and is expressed at high levels in the liver, kidneys, muscles, and heart. The ALDH2*2 allele is found in up to 40% of East Asian populations, and has a significant impact on alcohol metabolism. Interestingly, several studies have shown that individuals with ALDH2 deficiency are more susceptible to liver inflammation after drinking alcohol. Furthermore, there is growing evidence of an association between ALDH2 deficiency and the development of cancers in the liver, stomach, colon, and lung. Isoflavone analogues are low molecular-weight compounds derived from plants, similar in structure and activity to estrogen in mammals, known as phytoestrogens. Recent studies have reported that isoflavone analogues have beneficial effects on the progression of ALD. This mini-review summarizes the current knowledge about the roles of isoflavone analogues in ALD and discusses the therapeutic potential of isoflavone analogues in liver pathophysiology. In particular, we highlight the significance of computational approaches in this field.

Minicell-forming Escherichia coli mutant with increased chemical production capacity and tolerance to toxic compounds.

Minicell, a small spherical form of bacterium produced by abnormal fission, possesses cytoplasmic constituents similar to those of the parental cell, except for genomic DNA. E. coli strains were engineered to produce minicells and value-added chemicals. Minicell-forming mutants showed enhanced tolerance to toxic chemicals and a higher intracellular NADH/NAD+ ratio than the wild-type. When toxic chemicals such as isobutanol, isobutyraldehyde, and isobutyl acetate were produced in this mutant, the titers increased by 67 %, 175 %, and 214 %, respectively. In addition, morphological changes and membrane dispersion mechanisms in minicell-forming mutants improved lycopene production by 259 %. This increase in production capacity was more pronounced when biomass hydrolysate was used as the substrate. Isobutanol and lycopene production also increased by 92 % and 295 %, respectively, on using the substrate in the mutant. It suggests that minicell-forming mutants are an excellent platform for biochemical production.

Ethanol and its Nonoxidative Metabolites Promote Acute Liver Injury by Inducing ER Stress, Adipocyte Death, and Lipolysis.

BACKGROUND & AIMS: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model. METHODS: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. RESULTS: Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels. CONCLUSIONS: Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.

Deletion of adipocyte prohibitin 1 exacerbates high-fat diet-induced steatosis but not liver inflammation and fibrosis.

Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin-1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The PHB1 protein levels in adipose tissues were markedly decreased in mice fed a high-fat diet (HFD) compared to those fed a chow diet. To explore the function of adipocyte PHB1 in the progression of NAFLD, mice with adipocyte-specific (adipo) deletion of Phb1 (Phb1adipo-/- mice) were generated. Notably, Phb1adipo-/- mice did not develop obesity but displayed severe liver steatosis under HFD feeding. Compared to HFD-fed wild-type (WT) mice, HFD-fed Phb1adipo-/- mice displayed dramatically lower fat mass with significantly decreased levels of total adipose tissue inflammation, including macrophage and neutrophil number as well as the expression of inflammatory mediators. To our surprise, although liver steatosis in Phb1adipo-/- mice was much more severe, liver inflammation and fibrosis were similar to WT mice after HFD feeding. RNA sequencing analyses revealed that the interferon pathway was markedly suppressed while the bone morphogenetic protein 2 pathway was significantly up-regulated in the liver of HFD-fed Phb1adipo-/- mice compared with HFD-fed WT mice. Conclusion: HFD-fed Phb1adipo-/- mice display a subtype of the lean NAFLD phenotype with severe hepatic steatosis despite low adipose mass. This subtype of the lean NAFLD phenotype has similar inflammation and fibrosis as obese NAFLD in HFD-fed WT mice; this is partially due to reduced total adipose tissue inflammation and the hepatic interferon pathway.

Pharmacokinetic Comparison of Chitosan-Derived and Biofermentation-Derived Glucosamine in Nutritional Supplement for Bone Health.

Glucosamine and chondroitin sulfate have been used as nutritional supplementation for joint tissues and osteoarthritis (OA). Biofermented glucosamine is of great interest in the supplement industry as an alternative source of glucosamine. The purpose of this study is to compare the pharmacokinetics of chitosan-derived glucosamine and biofermentation-derived glucosamine as nutritional supplementation. In a randomized, double-blind and cross-over study design, we recruited subjects of healthy men and women. The pharmacokinetics of glucosamine were examined after a single dose of glucosamine sulfate 2KCl (1500 mg) with two different sources of glucosamine (chitosan-derived glucosamine and biofermentation-derived glucosamine) to male and female subjects fitted with intravenous (iv) catheters for repeated blood sampling up to 8 h. According to plasma concentration-time curve of glucosamine after an oral administration of 1500 mg of glucosamine sulfate 2KCl, AUC0-8h and AUC0-∞ values of glucosamine following oral administration of chitosan-derived and biofermentation-derived glucosamine formulations were within the bioequivalence criteria (90% CI of ratios are within 0.8-1.25). The mean Cmax ratios for these two formulations (90% CI of 0.892-1.342) did not meet bioequivalence criteria due to high within-subject variability. There were no statistically significant effects of sequence, period, origin of glucosamine on pharmacokinetic parameters of glucosamine such as AUC0-8h, AUC0-∞, Cmax. Our findings suggest that biofermentation-derived glucosamine could be a sustainable source of raw materials for glucosamine supplement.

Escherichia coli minicells with targeted enzymes as bioreactors for producing toxic compounds.

Formed by aberrant cell division, minicells possess functional metabolism despite their inability to grow and divide. Minicells exhibit not only superior stability when compared with bacterial cells but also exceptional tolerance-characteristics that are essential for a de novo bioreactor platform. Accordingly, we engineered minicells to accumulate protein, ensuring sufficient production capability. When tested with chemicals regarded as toxic against cells, the engineered minicells produced titers of C6-C10 alcohols and esters, far surpassing the corresponding production from bacterial cells. Additionally, microbial autoinducer production that is limited in expanding bacterial population was conducted in the minicells. Because bacterial population growth was nonexistent, the minicells produced autoinducers in constant amounts, which allowed precise control of the bacterial population having autoinducer-responsive gene circuits. When bacterial population growth was nonexistent, the minicells produced autoinducers in constant amounts, which allowed precise control of the bacterial population having autoinducer-based gene circuits with the minicells. This study demonstrates the potential of minicells as bioreactors suitable for products with known limitations in microbial production, thus providing new possibilities for bioreactor engineering.

Interplay between Solid Tumors and Tumor Microenvironment.

Over the past few decades, basic studies aimed at curing patients with cancer have been constantly evolving. A myriad of mechanistic studies on physiological changes and related factors in tumor growth and metastasis have been reported. Recently, several studies have been considerate to how tumors adapt to unfavorable environments, such as glucose deprivation, oxidative stress, hypoxic conditions, and immune responses. Tumors attempt to adapt to unfavorable environments with genetic or non-genetic changes, the alteration of metabolic signals, or the reconfiguration of their environment through migration to other organs. One of the distinct features in solid tumors is heterogeneity because their environments vary due to the characteristics of colony growth. For this reason, researchers are paying attention to the communication between growing tumors and neighboring environments, including stromal cells, immune cells, fibroblasts, and secreted molecules, such as proteins and RNAs. During cancer survival and progression, tumor cells undergo phenotype and molecular changes collectively referred to as cellular plasticity, which result from microenvironment signals, genetics and epigenetic alterations thereby contributing to tumor heterogeneity and therapy response. In this review, we herein discuss the adaptation process of tumors to adverse environments via communication with neighboring cells for overcoming unfavorable growth conditions. Understanding the physiology of these tumors and their communication with the tumor environment can help to develop promising tumor treatment strategies.

Impact of national Covid-19 vaccination Campaign, South Korea.

BACKGROUND: We evaluate the overall effectiveness of the nationwide vaccination campaign using ChAdOx1 nCoV-19, BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines in preventing Covid-19 in South Korea. METHODS: The National Surveillance System with the National Immunization Registry were linked to form a large-linked database for assessment. Age-adjusted incidence of SARS-CoV-2 infection, severe disease, and death by vaccination status are calculated. Weekly vaccine effectiveness was calculated based on incidence rate ratio (IRR) between fully-vaccinated and unvaccinated persons, as: IRR = incidence rate of vaccinated / incidence rate of unvaccinated. We estimate the cumulative SARS-CoV-2 outcome overtime comparing the observed case with predicted cases without vaccination. RESULTS: Age-adjusted incidence in unvaccinated persons (5.69 per 100,000 person-day) was 2.7 times the rate in fully vaccinated (2.13 per 100,000 person-day) persons, resulting effectiveness against SARS-CoV-2 infection of 63%. Vaccine effectiveness against severe disease and death were 93% and 95%, respectively. Between March and October 2021, estimated Covid-19 related outcomes averted by vaccinations were: 46,508 infections, 3,424 severe diseases, and 718 deaths. CONCLUSIONS: We found significant protection for national Covid-19 vaccination campaign against Covid-19 severe disease, and death in target populations, but there was an unexpected decreased protection against SARS-CoV-2 infection, highlighting the importance of continued surveillance and assessment.

Immune-related pathogenesis and therapeutic strategies of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and has become prevalent in the adult population worldwide, given the ongoing obesity pandemic. NAFLD comprises several hepatic disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), cirrhosis, and carcinoma. Excessive fat accumulation in the liver can induce the development of fatty liver, whereas the progression of fatty liver to NASH involves various complex factors. The crucial difference between fatty liver and NASH is the presence of inflammation and fibrosis, the emergence of which is closely associated with the action of immune cells and immunological factors, such as chemokines and cytokines. Thus, expanding our understanding of immunological mechanisms contributing to NASH pathogenesis will lead to the identification of therapeutic targets and the development of viable therapeutics against NASH.

Inhibitory effects of Rocaglamide-A on PPARγ-driven adipogenesis through regulation of mitotic clonal expansion involving the JAK2/STAT3 pathway.

Inhibition of adipogenesis is an important strategy for obesity treatment. Rocaglamide-A (Roc-A) is a natural herbal medicine isolated from the genus Aglaia (family Meliaceae), which has a cyclopenta[b]benzofuran core structure. Roc-A exhibits various pharmacological effects against diverse human cancer cells. However, the exact role of Roc-A during adipogenesis in adipocytes has not been studied at all. In this study, we demonstrate that Roc-A is crucial for reducing adipogenesis via downregulating PPARγ transcriptional activity. Consistently, Western-blot and RT-PCR analyses clearly showed that Roc-A inhibits the expression of PPARγ target genes and lipogenic markers in a dose-dependent manner along with suppression of lipid accumulation, in both 3T3-L1 cells and mouse adipose-derived stem cells. Mechanistically, Roc-A significantly decreased STAT3 phosphorylation in a dose-dependent manner in 3T3-L1 adipocytes. In particular, we confirmed that Roc-A effectively suppressed the expression of genes involved in cell-cycle regulation, such as cyclin A, B, D1, and E1, early during mitotic clonal expansion in 3T3-L1 adipocytes, and this effect was abolished by the JAK2/STAT3 activator FGF2. Taken together, our results demonstrated that Roc-A reduces adipogenesis by inhibiting PPARγ transactivation and STAT3 phosphorylation and thus may serve as a therapeutic target in obesity.

Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

SARS-CoV-2 Breakthrough Infections after introduction of 4 COVID-19 Vaccines, South Korea, 2021.

We conducted a nationwide retrospective cohort study to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection among recipients of 4 different vaccines in South Korea. Age-adjusted breakthrough infection rate per month was highest for Janssen (42.6/100,000 population), followed by AstraZeneca (21.7/100,000 population), Pfizer-BioNTech (8.5/100,000 population), and Moderna (1.8/100,000 population).