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The pathological identification of lymph node metastasis in whole-slide images is demanding and tedious. Here, the authors design an artificial-intelligence-assisted assessment workflow to facilitate the routine counting of metastatic LNs.

Abstract Background Cirrhosis is a chronic liver disease whereby scar tissue replaces healthy liver parenchyma, leading to disruption of the liver architecture and hepatic dysfunction. Currently, there is no effective disease-modifying therapy for liver fibrosis. Recently, our group demonstrated that human umbilical cord blood (UCB) plasma possesses therapeutic effects in a rat model of acute liver failure. Methods In the current study, we tested whether exosomes (Exo) existed in UCB plasma and if they produced any antifibrotic benefits in a liver fibrosis model. Results Our results showed that UCB-Exo improved liver function and increased matrix metalloproteinase/tissue inhibitor of metalloproteinase degradation to reduce the degree of fibrosis. Moreover, UCB-Exo were found to suppress hepatic stellate cell (HSC) activity in vitro. These effects were associated with suppression of transforming growth factor-β/inhibitor of DNA binding 1 signaling. Conclusions These results further support that UCB-Exo have antifibrotic effects in mice with liver fibrosis and activated HSCs and may herald a new cell-free antifibrotic therapy.

Objective: Aortic dissection is a rare but lethal disease. We demonstrate a rare case of acute complicated Stanford type A aortic dissection in the third trimester. Case report: A 41-year-old primiparous patient with chronic hypertension was brought to our emergency department at 34 weeks of gestation. She presented with acute tearing chest pain radiating to her back. Computed tomography revealed a Stanford type A aortic dissection. Primary cesarean section followed by open cardiovascular surgery was performed. However, ischemic bowels and bowel perforation occurred on the 9th and 11th postoperative days, respectively, and the patient died of septic shock on the 12th postoperative day. Conclusion: Aortic dissection must be taken into consideration for pregnant women with chronic hypertension who present with acute tearing chest pain and pulseless unilateral extremities. Bowel ischemia may occur in patients with complicated Stanford type A aortic dissection.

Pemphigus foliaceus (PF) is a chronic autoimmune blistering dermatosis (ABD) that often involves the face, scalp and trunk. Kaposi's varicelliform eruption (KVE) is a viral vesicular dermatosis that rarely complicates ABD. In addition, KVE infrequently causes ocular involvement including herpes simplex keratitis (HSK). Timely diagnosis of KVE may be difficult in patients with PF due to their overlapping clinical features. In this report, we described a 79-year-old female with PF complicated by KVE and bilateral HSK. This report reminds physicians that KVE should be considered in patients with refractory PF and other ABD.

Abstract This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)–signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1–STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery.

Hemophilia B (HB) is an inherited deficiency in coagulation factor IX (FIX) that leads to prolonged bleeding after injury. Although hepatocyte transplantation has been demonstrated to be an effective therapeutic strategy for HB, the quality and sources of hepatocytes still limit their application. Recently, stem cells were proposed as an alternative source of donor cells for cell-based therapy. Much research has been devoted to the properties of stem cells that can be differentiated into functional hepatocytes, thereby providing a new cell source for cell-based therapy. Induced pluripotent stem cells (iPSCs) represent a renewable source of hepatocytes for cell-based therapy; these cells exhibit pluripotency and differentiation ability and can be derived from somatic cells. These iPSCs are highly similar to embryonic stem cells (ESCs). We hypothesized that hepatocyte-like cells derived from iPSCs would have therapeutic efficiency in a mouse model of HB. To test this hypothesis, we differentiated iPSCs toward hepatocytes by stepwise protocol and then transplanted these cells into HB mice. We found that these cells shared many characteristics with hepatocytes, such as albumin synthesis, metabolic capacity, glycogen storage, and ureagenesis. Moreover, iPSC-derived hepatocyte transplantation led to increased coagulation factor IX activity, improved thrombus generation, and better hemostasis parameters, and the transferred cells were localized in the liver in recipient HB mice. In conclusion, our results clearly demonstrate that hepatocyte-like cells derived from iPSCs represent a potential cell source for cell-based therapy in the treatment of HB.

Hepatocyte transplantation (Tx) holds promise for curing genetic liver diseases. However, a limited number of donor hepatocytes can be transplanted into the host liver. Recipient preconditioning and donor cell engineering are under investigation to improve cell engraftment. In theory, genetically engineered cells secreting therapeutic proteins with superior function could compensate for poor engraftment efficiency. We have generated a bioengineered human coagulation factor IX (FIX) with augmented specific activity (named FIX-Triple). The aim of this study was to evaluate therapeutic efficacy of cell therapy using hemophilia B (HB) as a disease model by transplanting FIX-Triple-secreting hepatocytes. The donor hepatocytes were isolated from FIX-Triple knock-in (KI) or FIX-WT (wild-type) KI mice and transplanted intrasplenically into FIX knock-out (KO) mice. FIX-Triple KI recipients exhibited fourfold higher plasma FIX clotting activity than FIX-WT KI recipients. By repeated Txs, the clotting activity of FIX-Triple KI recipients even increased to more than 10% of normal mouse plasma. The engraftment and FIX production efficiencies of transplanted cells were equivalent between the FIX-WT KI and FIX-Triple KI donors. A hemostatic function assay showed that FIX-Triple KI recipients with repeated Txs had more enhanced clot kinetics and a greater maximum rate of thrombus generation than those with a single Tx. Moreover, FIX inhibitors in these recipients rarely developed. In conclusion, hepatocyte Tx with genetically engineered donor cells is an effective therapeutic strategy for HB.

PurposeThe purposes of this study were to determine whether biomechanical properties of mature oocytes could predict usable blastocyst formation better than morphological information or maternal factors, and to demonstrate the safety of the aspiration measurement procedure used to determine the biomechanical properties of oocytes.MethodsA prospective split cohort study was conducted with patients from two IVF clinics who underwent in vitro fertilization. Each patient's oocytes were randomly divided into a measurement group and a control group. The aspiration depth into a micropipette was measured, and the biomechanical properties were derived. Oocyte fertilization, day 3 morphology, and blastocyst development were observed and compared between measured and unmeasured cohorts. A predictive classifier was trained to predict usable blastocyst formation and compared to the predictions of four experienced embryologists.Results68 patients and their corresponding 1252 oocytes were included in the study. In the safety analyses, there was no significant difference between the cohorts for fertilization, while the day 3 and 5 embryo development were not negatively affected. Four embryologists predicted usable blastocyst development based on oocyte morphology with an average accuracy of 44% while the predictive classifier achieved an accuracy of 71%. Retaining the variables necessary for normal fertilization, only data from successfully fertilized oocytes were used, resulting in a classifier an accuracy of 81%.ConclusionsTo date, there is no standard guideline or technique to aid in the selection of oocytes that have a higher likelihood of developing into usable blastocysts, which are chosen for transfer or vitrification. This study provides a comprehensive workflow of extracting biomechanical properties and building a predictive classifier using these properties to predict mature oocytes' developmental potential. The classifier has greater accuracy in predicting the formation of usable blastocysts than the predictions provided by morphological information or maternal factors. The measurement procedure did not negatively affect embryo culture outcomes. While further analysis is necessary, this study shows the potential of using biomechanical properties of oocytes to predict embryo developmental outcomes.

Objectives: This study aimed to establish reference values for fetal aortic isthmus blood flow velocity and associated indices during the first trimester, utilizing a novel ultrasonographic technique known as high-definition flow imaging (HDFI). Additionally, the correlation between Doppler profiles of aortic blood flow and key fetal parameters, including nuchal thickness (NT), crown-rump length (CRL), and fetal heartbeat (FHB), was investigated. Methods: A total of 262 fetuses were included in the analysis between December 2022 and December 2023. Utilizing 2D power Doppler ultrasound images, aortic blood flow parameters were assessed, including aortic peak systolic velocity (PS), aortic end-diastolic velocity (ED), aortic time average maximal velocity (TAMV), and various indices such as aortic systolic velocity/diastolic velocity (S/D), aortic pulsatile index (PI), aortic resistance index (RI), aortic isthmus flow velocity index (IFI), and aortic isthmic systolic index (ISI). Concurrently, fetal FHB, NT, and CRL were evaluated during early trimester Down syndrome screening. Results: Significant findings include a positive correlation between gestational age (GA) and PS (PS = 3.75 × (GA) − 15.4, r2 = 0.13, p < 0.01), ED (ED = 0.42 × (GA) − 0.61, r2 = 0.04, p < 0.01), PI (PI = 0.07 × (GA) + 1.03, r2 = 0.04, p < 0.01), and TAMV (TAMV = 1.23 × (GA) − 1.66, r2 = 0.08, p < 0.01). In contrast, aortic ISI demonstrated a significant decrease (ISI = −0.03 × (GA) + 0.57, r2 = 0.05, p < 0.05) with gestational age. No significant correlation was observed for aortic RI (p = 0.33), S/D (p = 0.39), and IFI (p = 0.29) with gestational age. Aortic PS exhibited positive correlations with NT (0.217, p = 0.001) and CRL (0.360, p = 0.000) but a negative correlation with FHB (−0.214, p = 0.001). Aortic PI demonstrated positive correlations with CRL (0.208, p = 0.001) and negative correlations with FHB (−0.176, p = 0.005). Aortic TAMV showed positive correlations with NT (0.233, p = 0.000) and CRL (0.290, p = 0.000) while exhibiting a negative correlation with FHB (−0.141, p = 0.026). Aortic ISI demonstrated negative correlations with NT (−0.128, p = 0.045) and CRL (−0.218, p = 0.001) but a positive correlation with FHB (0.163, p = 0.010). Conclusions: Power Doppler angiography with Doppler ultrasound demonstrates the ability to establish accurate reference values for fetal aortic blood flow during the first trimester of pregnancy. Notably, aortic PS, TAMV, and ISI exhibit significant correlations with NT, CRL, and FHB, with ISI appearing more relevant than IFI, PS, TAMV, and FHB. The utilization of HDFI technology proves advantageous in efficiently detecting the site of the aortic isthmus compared to traditional color Doppler mode in early second trimesters.

Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for guiding clinical decisions on progesterone dosages to maximize reproductive outcomes. This retrospective study explored the utility of microRNA (miRNA) biomarkers in guiding personalized progesterone dosage adjustments for frozen embryo transfer (FET) cycles in 22 in vitro fertilization (IVF) patients undergoing hormone replacement therapy. Utilizing MIRA, an miRNA-based endometrial receptivity test, we analyzed patients’ miRNA expression profiles before and after progesterone dosage adjustments to determine suitable dosages and assess endometrial status. Despite patients receiving identical progesterone dosages, variations in miRNA profiles were observed in the initial cycle, and all patients presented a displaced window of implantation. Following dosage adjustments based on their miRNA profiles, 91% of patients successfully transitioned their endometrium towards the receptive stages. However, two patients continued to exhibit persistent displaced receptivity despite the adjustments. Given the evident variation in endometrial status and serum progesterone levels among individuals, analyzing miRNA expression profiles may address the challenge of inter-personal variation in serum progesterone levels, to deliver more personalized dosage adjustments and facilitate personalized luteal phase support in IVF.

Though tremendous advances have been made in the field of in vitro fertilization (IVF), a portion of patients are still affected by embryo implantation failure issues. One of the most significant factors contributing to implantation failure is a uterine condition called displaced window of implantation (WOI), which refers to an unsynchronized endometrium and embryo transfer time for IVF patients. Previous studies have shown that microRNAs (miRNAs) can be important biomarkers in the reproductive process. In this study, we aim to develop a miRNA-based classifier to identify the WOI for optimal time for embryo transfer. A reproductive-related PanelChip® was used to obtain the miRNA expression profiles from the 200 patients who underwent IVF treatment. In total, 143 out of the 167 miRNAs with amplification signals across 90% of the expression profiles were utilized to build a miRNA-based classifier. The microRNA-based classifier identified the optimal timing for embryo transfer with an accuracy of 93.9%, a sensitivity of 85.3%, and a specificity of 92.4% in the training set, and an accuracy of 88.5% in the testing set, showing high promise in accurately identifying the WOI for the optimal timing for embryo transfer.

Summary: Assisted reproductive technology (ART) is an important invention for the treatment of human infertility, and the isolation of high-quality sperm with progressive motility is one of the most critical steps that eventually affect the fertilization rate. Conventional sperm separation approaches include the swim-up method and density gradient centrifugation. However, the quality of isolated sperm obtained from both approaches can still be improved by improving sorted sperm motility, minimizing the DNA fragmentation rate, and removing abnormal phenotypes. Here, we report a Progressive Sperm Sorting Chip (PSSC) for high-quality sperm isolation. Based on the rheotaxis behavior of sperm, a gradient flow field is created in the chip for progressive sperm sorting. Clinical experiment results for 10 volunteers showed that greater than 90% of isolated sperm exhibit high motility (> 25 μm/s), high linearity (0.8), and a very low DNA fragmentation rate (< 5%). In addition, the whole process is label and chemical free. These features aid in gentle sperm sorting to obtain healthy sperm. This device uniquely enables the selection of high-quality sperm with progressive motility and might be clinically applied for infertility treatment in the near future.

MicroRNAs (miRNAs) can regulate the expression of genes involved in the establishment of the window of implantation (WOI) in the endometrium. Recent studies indicated that cell-free miRNAs in uterine fluid and blood samples could act as alternative and non-invasive sample types for endometrial receptivity analysis. In this study, we attempt to systematically evaluate whether the expression levels of cell-free microRNAs in blood samples could be used as non-invasive biomarkers for assessing endometrial receptivity status. We profiled the miRNA expression levels of 111 blood samples using next-generation sequencing to establish a predictive model for the assessment of endometrial receptivity status. This model was validated with an independent dataset (n = 73). The overall accuracy is 95.9%. Specifically, we achieved accuracies of 95.9%, 95.9%, and 100.0% for the pre-receptive group, the receptive group, and the post-respective group, respectively. Additionally, we identified a set of differentially expressed miRNAs between different endometrial receptivity statuses using the following criteria: p-value < 0.05 and fold change greater than 1.5 or less than −1.5. In conclusion, the expression levels of cell-free miRNAs in blood samples can be utilized in a non-invasive manner to distinguish different endometrial receptivity statuses.