Surgical Outcomes and Predictive Factors in Patients With Detrusor Underactivity Undergoing Bladder Outlet Obstruction Surgery.

PURPOSE: This study was conducted to evaluate the efficacy of bladder outlet surgery in patients with detrusor underactivity (DU) and to identify factors associated with successful outcomes. METHODS: We conducted a retrospective review of men diagnosed with DU in urodynamic studies who underwent bladder outlet surgery for lower urinary tract symptoms between May 2018 and April 2023. The International Prostate Symptom Score (IPSS) questionnaire, uroflowmetry (UFM), and multichannel urodynamic studies were administered. Successful treatment outcomes were defined as either an IPSS improvement of at least 50% or the regaining of spontaneous voiding in patients urethral catheterization prior to surgery. RESULTS: The study included 93 male patients. Men diagnosed with significant or equivocal bladder outlet obstruction (BOO) experienced significant postoperative improvements in IPSS (from 20.6 to 6.0 and from 17.4 to 6.5, respectively), maximum urine flow rate (from 5.0 mL/sec to 14.4 mL/sec and from 8.8 mL/sec to 12.2 mL/sec, respectively) and voiding efficiency (from 48.8% to 86.0% and from 61.2% to 85.1%, respectively). However, in the group without obstruction, the improvements in IPSS and UFM results were not significant. The presence of detrusor overactivity (odds ratio [OR], 3.152; P=0.025) and preoperative urinary catheterization (OR, 2.756; P=0.040) were associated with favorable treatment outcomes. Conversely, an unobstructed bladder outlet was identified as a negative prognostic factor. CONCLUSION: In men with DU accompanied by equivocal or significant BOO, surgical intervention to alleviate the obstruction may enhance the IPSS, quality of life, and UFM results. However, those with DU and an unobstructed bladder outlet face a comparatively high risk of treatment failure. Preoperative detrusor overactivity and urinary catheterization are associated with more favorable surgical outcomes. Consequently, active deobstructive surgery should be considered for patients with DU who are experiencing urinary retention.

Association between chronic prostatitis and the subsequent benign prostatic hyperplasia: a population-based national cohort study.

PURPOSE: To explore the association between chronic prostatitis (CP) and the subsequent development of benign prostatic hyperplasia (BPH). METHODS: Data analyzed were medical claims of Taiwan's National Health Insurance program. From 2010 to 2017, 3571 patients ≧20 years with CP diagnosed by certified urologists were enrolled. Patients with past BPH diagnosis and diagnosis of prostate cancer, inguinal hernia, interstitial cystitis, and urethritis in the past and within one year after the first CP diagnosis were excluded. Age-matched controls were randomly selected from all non-CP individuals of the same exclusion criteria in the study period with a CP/non-CP ratio of 1:4. The follow-up was made from the first CP diagnosis to death or the end of 2018. The endpoint was the newly diagnosed BPH. Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of BPH in association with CP. RESULTS: Over a maximum of 8 years of follow-up, 287 (8.03%) and 258 (0.43%) BPH events were noted for the CP and non-CP group, respectively, representing a covariate adjusted HR (aHR) of 4.30 (95% CI, 3.61-5.13). Younger patients tended to suffer from higher aHRs, especially those aged 20-39 years (aHR: 11.45, 95% CI, 5.12-25.64). CONCLUSION: The Taiwan national health database indicated that CP patients had a significantly higher risk of developing BPH later than non-CP patients. Interestingly, the younger the CP is diagnosed (under 40), the greater the risk.

Therapeutic efficacy of 180-W GreenLight laser photoselective vaporization of the prostate for storage symptoms concomitant with benign prostatic obstruction and a search for outcome predictors.

PURPOSE: Benign prostatic obstruction (BPO) is the most common cause of lower urinary tract symptoms among men. GreenLight photoselective vaporization of the prostate (GL-PVP) using a 180-W Xcelerated performance system (XPS) laser is a well-established method for treating BPO-induced voiding symptoms. However, its therapeutic effects on storage symptoms remain unclear. This study aimed to analyze the storage outcomes in patients who underwent 180-W XPS GL-PVP for BPO and to identify outcome predictors. MATERIALS AND METHODS: Patients who underwent 180-W XPS GL-PVP for BPO between May 2018 and May 2021 were retrospectively reviewed. Data on clinical characteristics, prostate volume, preoperative and postoperative International Prostate Symptom Scores (IPSS), and preoperative urodynamic parameters were collected. A favorable storage outcome was defined as ≥50% reduction in the IPSS storage subscore. RESULTS: Ninety-nine male patients were included, with a mean age of 69.4 ± 9.6 years and a baseline prostatic volume of 75.9 ± 33.1 mL. The IPSS total, storage, and voiding subscores significantly decreased after GL-PVP (all p < 0.001). Seventy-two patients achieved favorable storage outcome at 6 months. Multivariate analysis revealed that detrusor underactivity was predictive of unfavorable storage outcomes (p = 0.022), while IPSS voiding-to-storage subscore ratio >1.25 and the presence of detrusor overactivity were predictive of favorable storage outcomes (p = 0.008 and 0.033, respectively). CONCLUSION: 180-W XPS GL-PVP provided excellent outcomes in both voiding and storage lower urinary tract symptoms concomitant with BPO. Preoperative IPSS and multichannel urodynamic parameters including detrusor overactivity and underactivity are valuable predictors of postoperative storage outcomes.

MicroRNA-320a enhances LRWD1 expression through the AGO2/FXR1-dependent pathway to affect cell behaviors and the oxidative stress response in human testicular embryonic carcinoma cells.

BACKGROUND: Testicular cancer is fairly rare but can affect fertility in adult males. Leucine-rich repeats- and WD repeat domain-containing protein 1 (LRWD1) is a sperm-specific marker that mainly affects sperm motility in reproduction. Our previous study demonstrated the impact of LRWD1 on testicular cancer development; however, the underlying mechanisms remain unclear. METHODS: In this study, various plasmids associated with LRWD1 and miR-320a manipulation were used to explore the roles and regulatory effects of these molecules in NT2D1 cellular processes. A Dual-Glo luciferin-luciferase system was used to investigate LRWD1 transcriptional activity, and qRT-PCR and western blotting were used to determine gene and protein expression. RESULTS: The results suggested that miR-320a positively regulated LRWD1 and positively correlated with NT2D1 cell proliferation but negatively correlated with cell migration and invasion ability. In addition, the miRNA-ribonucleoprotein complex AGO2/FXR1 was shown to be essential in the mechanism by which miR-320a regulates LRWD1 mRNA expression. As miR-320a was required to regulate LRWD1 expression through the AGO2 and FXR1 complex, eEF2 and eLF4E were also found to be involved in miR-320a increasing LRWD1 expression. Furthermore, miR-320a and LRWD1 were responsive to oxidative stress, and NRF2 was affected by the presence of miR-320a in response to ROS stimulation. CONCLUSIONS: This is the first study showing the role of miR-320a in upregulating the testicular cancer-specific regulator LRWD1 and the importance of the AGO2/FXR1 complex in miR-320a-mediated upregulation of LRWD1 during testicular cancer progression.

lncRNA TMEM161B-AS1 screened the onset of oral squamous cell carcinoma in HPV-infected patients, predicted poor prognosis, and regulated cell progression via modulating the miR-651-5p/BDNF axis.

Oral squamous cell carcinoma (OSCC) has become the most common HPV-related cancer with high invasion and metastasis. Exploring biomarkers for the screening and monitoring of OSCC, especially for the HPV-OSCC, would benefit patients' diagnosis and prognosis. This study evaluated the significance and mechanism of TMEM161B-AS1 and miR-651-5p in HPV-OSCC aiming to provide novel insight into the mechanism of HPV-OSCC development. Expression of TMEM161B-AS1 and miR-561-5p was analyzed in healthy individuals, HPV-infected non-OSCC patients, and HPV-OSCC patients using PCR. Their significance in HPV-OSCC occurrence and prognosis was evaluated by logistic regression, ROC, Kaplan-Meier, and Cox regression analysis. In OSCC cells, CCK8 and Transwell assays were employed for assessing cell growth and metastasis. The luciferase reporter assay and cell transfection were performed to evaluate the regulatory association between TMEM161B-AS1, miR-561-5p, and BDNF. Significant upregulation of TMEM161B-AS1 and downregulation of miR-561-5p were observed in oral HPV-infected patients. Both TMEM161B-AS1 and miR-651-5p served as risk factors for the occurrence of OSCC in oral HPV-infected patients and could distinguish HPV-OSCC patients from HPV-infected non-OSCC patients. Increased TMEM161B-AS1 and reduced miR-561-5p indicated severe development and adverse prognosis of HPV-OSCC patients. In OSCC cells, silencing TMEM161-AS1 suppressed cell proliferation and motility via negatively modulating miR-561-5p. miR-561-5p negatively regulated BDNF, which was considered the underlying mechanism of TMEM161B-AS1. Increasing TMEM161B-AS expression and decreasing miR-561-5p showed the occurrence of OSCC in HPV-infected patients and predicted malignant development and adverse prognosis. TMEME161B-AS1 served as a tumor promoter via regulating the miR-561-5p/BDNF axis.

Male infertility.

Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30-50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.

Intravenous Polymyxin B as Adjunctive Therapy to High-Dose Tigecycline for the Treatment of Nosocomial Pneumonia Due to Carbapenem-Resistant Acinetobacter baumannii and Klebsiella pneumoniae: A Propensity Score-Matched Cohort Study.

Although the combination of polymyxin and tigecycline is widely used in treating carbapenem-resistant bacterial infections, the benefit of this combination is still uncertain. To assess whether adding polymyxin B to the high-dose tigecycline regimen would result in better clinical outcomes than the high-dose tigecycline therapy in patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, we conducted a propensity score-matched cohort study in a single center between July 2019 and December 2021. Of the 162 eligible patients, 102 were included in the 1:1 matched cohort. The overall 14-day mortality in the matched cohort was 24.5%. Compared with high-dose tigecycline, the combination therapy was not associated with better clinical outcomes, and showed similar 14-day mortality (OR, 0.72, 95% CI 0.27-1.83, p = 0.486), clinical cure (OR, 1.09, 95% CI 0.48-2.54, p = 0.823), microbiological cure (OR, 0.96, 95% CI 0.39-2.53, p = 0.928) and rate of nephrotoxicity (OR 0.85, 95% CI 0.36-1.99, p = 0.712). Subgroup analyses also did not demonstrate any statistical differences. Based on these results, it is reasonable to recommend against adding polymyxin B to the high-dose tigecycline regimen in treating pneumonia caused by carbapenem-resistant K. pneumoniae and A. baumannii.

Influence of inflammation on bleeding and wound healing following surgical extraction of impacted lower third molars.

OBJECTIVE: This study aimed to investigate the effect of inflammatory states following impacted lower third molar (ILTM) surgery regarding postoperative bleeding and wound healing. METHODS: The study included patients who underwent extraction of ILTMs associated with or without inflammatory conditions. Post-extraction bleeding and wound healing were assessed. In addition, mean grey values (MGVs) of alveolar bone and bone height using an orthopantomography radiograph were analyzed. RESULTS: A total of 376 patients were enrolled; 171 pericoronitis, 51 pulpitis, 44 chronic periapical periodontitis, 36 chronic periodontitis, and 74 control. The bleeding score in the control group was significantly lower than in the periapical periodontitis and periodontitis groups. Excellent wound healing for control, pericoronitis, pulpitis, periapical periodontitis, and periodontitis groups was (78.38%, 35.67%, 70.59%, 70.45%, and 33.33%, respectively). Patients with pericoronitis and periodontitis had significantly poorer wound healing (P < 0.01). The MGV in periapical periodontitis and periodontitis was considerably lower than in the control group. CONCLUSIONS: The inflammatory conditions associated with ILTMs increase the risk of bleeding. So suturing with the placement of local hemostatic agents over a pressure pack alone is recommended. The poorest wound healing was in localized gingival inflammation. Furthermore, MGV was affected by age and was lower with periapical periodontitis.

The MAEL expression in mitochondria of human spermatozoa and the association with asthenozoospermia.

PURPOSE: The maelstrom spermatogenic transposon silencer (MAEL) function in postmeiotic germ cells remains unclear, and its protein localization in human testis and spermatozoa awaits determination. This study aims to clarify the MAEL expression in human spermatogenesis and to explore its role in sperm function. MATERIALS AND METHODS: Twenty-seven asthenozoospermic men, 40 normozoospermic controls, and three obstructive azoospermic men were enrolled. The transcripts of MAEL in the seminiferous epithelium and MAEL downstream targets were identified by bioinformatics analysis. MAEL protein expression in human testis and ejaculated sperms were examined by immunohistochemical and immunogold staining, respectively. The roles of MAEL in mitochondria function were investigated by siRNA knockdown in human H358 cells. The association between MAEL protein levels and clinical sperm features was evaluated. RESULTS: Abundant MAEL was expressed in spermatid and spermatozoa of the human testis. Remarkably, MAEL was located in the mitochondria of ejaculated sperm, and bioinformatics analysis identified GPX4 and UBL4B as MAEL's downstream targets. Knockdown of MAEL sabotaged mitochondria function and reduced adenosine triphosphate (ATP) production in H358 cells. MAEL, GPX4, and UBL4B expression levels were significantly decreased in asthenozoospermic sperms than in controls. The MAEL protein levels were positively correlated with GPX4 and UBL4B in human sperm. Total motile sperm count (TMSC) was positively correlated with protein levels of MAEL, GPX4, and UBL4B in ejaculated sperms. CONCLUSIONS: We highlight prominent MAEL expression in the intratesticular spermatid and the mitochondria of ejaculated spermatozoa. MAEL directly binds to GPX4 and UBL4B, and loss of MAEL induces mitochondrial dysfunction. MAEL-mitochondrial function-motility relationship might advance our understanding of the causes of asthenozoospermia.

The Association between Monthly, Yearly, and Lifetime Cannabis Use, and Semen Parameters in Asian-American Men.

PURPOSE: Medicinal and recreational cannabis use has grown exponentially, however, its effect on testicular function and spermatogenesis remains uncertain. The aim of this study was to evaluate the association between cannabis use and semen parameters in a cohort of Asian-American men with unknown fertility. MATERIALS AND METHODS: Asian men were recruited to complete an online survey and submit a semen sample. Semen analysis, demographic data, lifestyle factors, and cannabis use habits were collected. Linear and logistic regression analyses were used to determine. RESULTS: Among the 112 men included in this study, 51 used cannabis at least once in their lifetime, 30 men used cannabis at least once in the last 12 months, and 26 men used cannabis at least once in the last 30 days. Adjusted linear regression analyses identified an association between cannabis use in the previous 30 days and worse sperm morphology (ß: -0.45, p=0.025) and sperm motility (ß: -1.64, p=0.016). However, when stratifying by subfertile semen quality (i.e., WHO criteria), no association was identified between semen quality and cannabis use. Lower sperm morphology and motility are partially associated with recent cannabis use, while all other semen parameters are not. CONCLUSIONS: We did not observe any consistent associations between cannabis use on any semen parameters in Asian-American men. Further studies within the field are needed to explore racial and ethnic differences in semen quality and lifestyle factors.

The Interaction Between SMAD1 and YAP1 Is Correlated with Increased Resistance of Gastric Cancer Cells to Cisplatin.

Drug resistance is a major obstacle leading to treating failure and poor outcome in gastric cancer (GC). This study explores the interaction between SMAD family member 1 (SMAD1) and Yes1-associated transcriptional regulator (YAP1) and their roles in cisplatin (DDP) resistance in GC. Transcriptome analysis predicted that SMAD1 is highly expressed in DDP-resistant cells. Elevated SMAD1 expression was detected in GC tissue and cells, especially in DDP-resistant cells (MKN-45/DDP and AGS/DDP). SMAD1 downregulation in cells decreased 50% inhibition value of DDP, reduced proliferation, migration, and invasion, and promoted cell cycle arrest and apoptosis. A protein-protein interaction network suggested a possible SMAD1 and YAP1 interaction in GC. The SMAD1 and YAP1 interaction was validated by chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and luciferase assays. SMAD1 bound to YAP1 and activated its transcription. SMAD1 formed complexes with YAP1 in nucleus, and YAP1 upregulation enhanced SMAD1 activity as well. Upregulation of YAP1 restored the malignant behaviors of GC cells suppressed by SMAD1 silencing. In vivo, SMAD1 silencing suppressed growth and DDP resistance of xenograft tumors in nude mice, and this suppression was blocked by YAP1 overexpression again. In conclusion, this study demonstrates that SMAD1 can interact with YAP1 to enhance the DDP resistance of GC cells.

The sufficient multidisciplinary specialists under a government-led health care system associated with the downward mortality trend of Fournier's gangrene in Taiwan.

OBJECTIVES: To explore the trends in Fournier's gangrene (FG) incidence and mortality rate in Taiwan and to investigate the contributing factors to such changes. METHODS: Between 2002 and 2016, hospitalized FG patients who underwent subsequent surgical intervention were included in this retrospective study. Incidence, outcomes, age-adjusted Charlson Comorbidity Index (ACCI), hospitalization cost, surgical timing, and the number of multidisciplinary specialists involved in the first-line management of FG in each year were collected. Simple linear regression and Pearson correlation coefficient (r) were used for the subsequent analysis. RESULTS: The national cohort enrolled 2183 FG patients from 2002 to 2016 in Taiwan. The age-standardized incidence rate of FG was between 0.4 and 0.8 per 100 000 population, and overall mortality was 7.8% in these 15 years. We illustrated the downward trendline of FG mortality with a 0.62 coefficient of determination. The mortality of FG patients who underwent surgery within 24 h and after 24 h were found to be 8.3 ± 3.9% and 14.6 ± 25.2%, respectively (p = 0.02). The numbers of urologists, anesthesiologists, emergency doctors, and physicians per 100 000 population had a strong negative linear correlation with FG mortality (r = 0.8, p < 0.001). ACCI score had a moderate linear relationship with FG mortality (r = 0.57, p = 0.027). The hospitalization cost showed a weak linear correlation with FG mortality (r = -0.03, p = 0.92). CONCLUSIONS: We demonstrated the downward trend of the FG mortality rate in Taiwan from 2002 to 2016. Besides underlying comorbidities and surgical timing, sufficient multidisciplinary specialists are essential for the survival benefit of FG patients in Taiwan experience.

Advanced nanomaterial for prostate cancer theranostics.

Prostate cancer (PC) has the second highest incidence in men, according to global statistical data. The symptoms of PC in the early stage are not obvious, causing late diagnosis in most patients, which is the cause for missing the optimal treatment time. Thus, highly sensitive and precise early diagnosis methods are very important. Additionally, precise therapy regimens for good targeting and innocuous to the body are indispensable to treat cancer. This review first introduced two diagnosis methods, containing prostate-specific biomarkers detection and molecular imaging. Then, it recommended advanced therapy approaches, such as chemotherapy, gene therapy, and therapeutic nanomaterial. Afterward, we summarized the development of nanomaterial in PC, highlighting the importance of integration of diagnosis and therapy as the future direction against cancer.

Circadian clock gene Clock-Bmal1 regulates cellular senescence in Chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease. COPD is associated with accelerated lung aging. Circadian clock is believed to play important roles in COPD. Although the circadian molecular clock regulates cellular senescence, there is no information available regarding the impact of COPD. The aim of this study is to investigate the role of the circadian clock protein BMAL1 and CLOCK in cellular senescence in order to understand the cellular mechanisms of accelerated aging of COPD. Bmal1 and Clock levels were assessed in the plasma samples of non-smokers, smokers, and patients with COPD. The regulation of ciracadian clock expression and cell senescence by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and overexpression of Bmal1 or Clock were employed to investigate the role of circadian clock on cell senescence. Herein, patients with COPD showed lower Bmal1 and Clock expression in the plasma. Interestingly, CSE exposure contributed to the increased cell senescence, decreased Clock and Bmal1 in human bronchial epithelial cells (Beas-2B cells). We found that knockdown of Clock or Bmal1 lead to upregulation of cell senescence in Beas-2B cells, while overexpression of Clock or Bmal1 inhibited cell senescence in Beas-2B cells, which is through the MAPK pathways. Therefore, our findings indicated that Bmal1 or Clock deficiency may be a significant factor to increase cellular senescence of the lung to develop COPD.

Site specific NMR characterization of abeta-40 oligomers cross seeded by abeta-42 oligomers.

Extracellular accumulation of ß amyloid peptides of 40 (Aß40) and 42 residues (Aß42) has been considered as one of the hallmarks in the pathology of Alzheimer's disease. In this work, we are able to prepare oligomeric aggregates of Aß with uniform size and monomorphic structure. Our experimental design is to incubate Aß peptides in reverse micelles (RMs) so that the peptides could aggregate only through a single nucleation process and the size of the oligomers is confined by the physical dimension of the reverse micelles. The hence obtained Aß oligomers (AßOs) are 23 nm in diameter and they belong to the category of high molecular-weight (MW) oligomers. The solid-state NMR data revealed that Aß40Os adopt the structural motif of ß-loop-ß but the chemical shifts manifested that they may be structurally different from low-MW AßOs and mature fibrils. From the thioflavin-T results, we found that high-MW Aß42Os can accelerate the fibrillization of Aß40 monomers. Our protocol allows performing cross-seeding experiments among oligomeric species. By comparing the chemical shifts of Aß40Os cross seeded by Aß42Os and those of Aß40Os prepared in the absence of Aß42Os, we observed that the chemical states of E11, K16, and E22 were altered, whereas the backbone conformation of the ß-sheet region near the C-terminus was structurally invariant. The use of reverse micelles allows hitherto the most detailed characterization of the structural variability of Aß40Os.

Incorporating sperm DNA fragmentation index with computer-assisted semen morphokinematic parameters as a better window to male fertility.

This study aimed to assess (1) the reproducibility of three sperm chromatin dispersion (SCD) assays for sperm DNA fragmentation, i.e., LensHooke R10® (R10), Halosperm G2® (G2), and BASO® (BA); (2) the correlation between computer-assisted semen analyzer (CASA) morphokinematic parameters and sperm DNA fragmentation index (DFI), and (3) the diagnostic value for male reproduction by combining semen morphokinematic parameters and DFI. Total 50 male participants were recruited, and all collected semen samples underwent semen analyses and SCD assays. Intra- and inter-observer variability of DFI data from different SCD measures was tested. In addition, the predictive ability of CASA parameters and DFI (with different cutoffs, i.e., 15% and 20%) for infertility was assessed using receiver operating characteristic curve analysis. We found that the G2 and R10 produced satisfactory variance coefficients (5.53%, 5.67%) compared to BA (14.8%). The DFI data from the R10 had lower intra-observer variability, in terms of higher intra-class coefficient (0.9615), than that of the G2 (0.8847) or BA (0.8824). Inter-observer variability of three SCD kits in scoring the DFI was comparable and satisfactory (concordance correlation coefficients ranging 0.9895-0.9630). The CASA parameters (i.e., total motility [r = -0.57], progression motility [r = -0.55], and rapidly progressive motility [r = -0.55]) were significantly correlated with DFI (P < 0.001). The predictive ability of the 15%-cutoff DFI data was better than that of the 20%-cutoff or continuous DFI data. The model comprising the CASA parameters, 15%-cutoff DFI, and 4%-cutoff normal morphology had the highest area under curve (0.8125) for infertility. For SCD assay, the R10 was the most reliable SCD assay to detect sperm DNA fragmentation. Combining the sperm DFI with CASA parameters might be a better diagnostic tool for male reproduction.

An Injectable Epigenetic Autophagic Modulatory Hydrogel for Boosting Umbilical Cord Blood NK Cell Therapy Prevents Postsurgical Relapse of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.

The Main Pulmonary Artery to the Ascending Aorta Diameter Ratio (PA/A) as a Predictor of Worse Outcomes in Hospitalized Patients with AECOPD.

Purpose: The main pulmonary artery (PA) to ascending aorta diameter ratio (PA/A) greater than one is a promising indicator of pulmonary hypertension (PH) in acute exacerbation (AE) of chronic obstructive pulmonary disease (COPD) (AECOPD). This study aims to disclose the associations between the PA/A ratio and clinical outcomes in hospitalized patients with AECOPD. Patients and Methods: Consecutive AECOPD patients admitted to the Department of Respiratory Medicine from September 2017 to July 2021 were reviewed. The treatment success of AECOPD patients was defined as improvement in the clinical condition when discharged from the hospital. Conversely, treatment failure was considered to be an event of in-hospital death or deterioration of the clinical condition prior to discharge. Results: A total of 118 individuals were ultimately reviewed in this study: 74 individuals with a PA/A ratio <1 and 44 individuals with a PA/A ratio ≥1. The outcomes of 21 patients were treatment failure, and 97 patients were considered successes. Patients with a PA/A ratio ≥1 had significantly higher PaCO2, red cell distribution width, brain natriuretic peptide, PA diameters, RICU admission rates, and proportions of treatment failure than patients with PA/A ratios <1 (P < 0.05). The PA diameter and PA/A ratio were significantly increased in the treatment failure group compared with the success group (P < 0.05). A survival analysis indicated that patients with a PA/A ratio ≥1 had worse outcomes than patients with a PA/A ratio <1 during hospitalization (P < 0.05). A multivariate analysis showed that a PA/A ratio ≥1 was an independent risk factor for treatment failure in patients with AECOPD. Conclusions: AECOPD patients with a PA/A ratio ≥1 may have worse outcomes during hospitalization. A PA/A ratio ≥1 may be a promising predictor of treatment failure in patients with AECOPD.

Injectable adhesive hemostatic gel with tumor acidity neutralizer and neutrophil extracellular traps lyase for enhancing adoptive NK cell therapy prevents post-resection recurrence of hepatocellular carcinoma.

Post-resection recurrence remains an intractable problem in hepatocellular carcinoma (HCC) management. Natural killer (NK) cell infusion is considered as a promising cancer therapy, but acidic tumor microenvironment (TME) and neutrophil extracellular traps (NETs) greatly counteract its efficacy. Recently, polymer hydrogels have aroused much interest in tumor combination therapy, since they load and controllably release therapeutic agents with high bioavailability and low systemic toxicity. Therefore, a biocompatible hydrogel with tumor acidity neutralizer and NETs lyase may show promise for enhancing NK infusion to prevent post-resection HCC recurrence. Herein, a dual pH-responsive hydrogel with tumor acidity neutralizer (mesoporous bioactive glass nanoparticles) and NETs lyase (Deoxyribonuclease I, DNase I) is developed and used in combination with NK cell infusion for preventing post-resection HCC recurrence. The hydrogel can be injected to surgical margin and form an adhesive gel with a rapid hemostasis. Besides, it neutralizes tumor acidity to reduce tumor infiltration of immunosuppressive cells, and releases DNase I in a pH-responsive manner to degrade NETs. Moreover, this combination therapy significantly enhances NK cell infusion to combat post-surgical HCC recurrence without systemic toxicity. This study provides proof of concept that combination of NK cell adoptive therapy and hydrogel-based delivery system can successfully prevent post-resection HCC recurrence.

Clinical significance of procalcitonin in critically ill patients with pneumonia receiving bronchoalveolar lavage.

Background: As a useful tool in intensive care units (ICU), fiberoptic bronchoscopy (FOB) may cause a deterioration of infection. This study is to investigate the clinical significance of procalcitonin (PCT) in critically ill patients with severe pneumonia receiving bronchoalveolar lavage (BAL). Methods: A retrospective case-control study was performed in a single respiratory ICU (RICU) with 6-bed. Critically ill patients with severe pneumonia admitted to RICU were consecutively reviewed from March 2017 to October 2019. Chi-square test, Wilcoxon test, Mann Whitney U-test, Kaplan-Meier survival analysis or Cox's proportional hazards regression model was used as appropriate. Results: A total of 72 eligible patients were included in the final analysis, 51 of which received BAL performed by FOB. Serum levels of PCT in group received BAL is markedly increased at 24 hours after FOB (p<0.001). Forty-eight hours later, BAL group with decreased serum levels of PCT had less SOFA score and decreased mortality compared with those with increased serum levels of PCT. Furthermore, Kaplan-Meier analysis indicated that patients with decreased serum levels of PCT had improved survival rate during hospital (Breslow test, p=0.041). However, increased PCT after BAL was not an independent risk factor for in-hospital mortality (hazard ratio: 1.689, 95% CI(0.626 ,4.563), p=0.301). Conclusions: BAL performed by FOB increased serum levels of PCT. However, PCT levels decreased at 48 hours after BAL predicted a good prognosis of patients with severe pneumonia.