Analysis of uroseptic shock after ureteroscopy for ureteral calculi during pregnancy: a case report.

BACKGROUND: Uroseptic shock secondary to ureteral calculi during pregnancy is rare. It is characterized by rapid onset, rapid progression, aggressive disease, limited treatment, poor prognosis, and a mortality rate higher than 20% with improper or delayed management. A clear diagnosis is made based on typical clinical symptoms and abdominal ultrasound, often requiring combined multidisciplinary treatment and the simultaneous release of the obstruction. The high mortality rate is mainly related to inappropriate early treatment of stones and infections or failure to intervene in a timely manner. CASE PRESENTATION: A 21-year-old first-time pregnant patient with uroseptic shock was admitted to our intensive care unit. The patient was successfully treated at our hospital with multidisciplinary cooperation, high-dose vasoactive drugs, IABP, CRRT, VA-ECMO, and termination of pregnancy. CONCLUSIONS: Timely relief of obstructions, termination of pregnancy, and the provision of IABP, CRRT, and VA-ECMO when necessary in critically ill patients with uroseptic shock during pregnancy can improve the success rate of resuscitation.

Management of Greenstick Fracture at the Root of Adult Zygomatic Arch.

Greenstick fractures mostly occur in children and rarely in adults. In adult zygomaticomaxillary complex fractures, the greenstick fracture at the root of the zygomatic arch is occasionally encountered. This makes it difficult to move the fracture segment. Therefore, achieving anatomic reduction is very difficult. Our preoperative 3D repaired model shows that if only the maxilla and zygomatic bones are restored, the patient's face will still have depression and protrusion. The greenstick fracture segment at the root of the zygomatic arch needs to undergo osteotomy to achieve anatomic reduction and restore facial symmetry. The patient's facial appearance was restored after the surgery. The postoperative computed tomography scan showed good alignment of the fracture. The authors believe that a fracture at the root of the zygomatic arch can serve as an indication for open reduction and fixation.

The long noncoding RNA Arrl1 inhibits neurite outgrowth by functioning as a competing endogenous RNA during neuronal regeneration in rats.

The intrinsic regeneration ability of neurons is a pivotal factor in the repair of peripheral nerve injury. Therefore, identifying the key modulators of nerve regeneration may help improve axon regeneration and functional recovery after injury. Unlike for classical transcription factors and regeneration-associated genes, the function of long noncoding RNAs (lncRNAs) in the regulation of neuronal regeneration remains mostly unknown. In this study, we used RNA-Seq-based transcriptome profiling to analyze the expression patterns of lncRNAs and mRNAs in rat dorsal root ganglion (DRG) following sciatic nerve injury. Analyses using the lncRNA-mRNA co-expression network, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway databases indicated that the lncRNA Arrl1 decreases neurite outgrowth after neuronal injury. shRNA-mediated Arrl1 silencing increased axon regeneration both in vitro and in vivo and improved functional recovery of the sciatic nerve. Moreover, inhibiting an identified target gene of Arrl1, cyclin-dependent kinase inhibitor 2B (Cdkn2b), markedly promoted neurite outgrowth of DRG neurons. We also found that Arrl1 acts as a competing endogenous RNA that sponges a Cdkn2b repressor, microRNA-761 (miR-761), and thereby up-regulates Cdkn2b expression during neuron regeneration. We conclude that the lncRNA Arrl1 affects the intrinsic regeneration of DRG neurons by derepressing Cdkn2b expression. Our findings indicate a role for an lncRNA-microRNA-kinase pathway in the regulation of axon regeneration and functional recovery following peripheral nerve injury in rats.

Recommended Management of Temporomandibular Joint Dislocation During the COVID-19 Outbreak.

The epidemic of coronavirus disease 2019 (COVID-19) has become a major public health disaster worldwide. From January 23 to March 20, total 17 patients with TMJ dislocation were treated in dental emergency department in School and Hospital of Stomatology, Wuhan University. Almost half of the patients are older than 80 years of age and they have recurrent joint dislocations. They are also at high risk for the COVID-19. The supine position technique method is suggested. The authors consider it necessary to recommend a practical management for TMJ dislocation.

Role of Calprotectin as a Biomarker in Periodontal Disease.

Periodontal disease (PD) is a common infectious and inflammatory disease characterised by inflammation of tissues surrounding and supporting the teeth and destruction of the associated alveolar bone, eventually resulting in tooth loss. This disease is caused by periodontopathic bacteria in plaque biofilm and resultant innate and adaptive immune responses in periodontal tissues. Calprotectin (CLP) is a calcium-binding protein of the S-100 protein family and is found to be induced by activated granulocytes, monocytes, and epithelial cells. CLP has been shown to play an important role in numerous inflammatory diseases and disorders. Increasing evidence indicates that CLP is involved in the progression of PD, and its levels may be associated with disease severity and outcome of periodontal treatments. This review will summarise recent studies regarding the presence, regulation, and function of CLP in PD. The findings indicate that CLP may be an effective biomarker for diagnosis and treatment for the PD.

Clinical Trial of Manual Reduction of Temporomandibular Joint Dislocation After Inhalation of Nitrous Oxide.

OBJECTIVE: The aim of this study was to evaluate the efficiency of inhaled nitrous oxide (N2O) for manual reduction of acute nontraumatic temporomandibular joint (TMJ) dislocation in the supine position technique. METHODS: This clinical trial included a total of 51 patients presenting with acute nontraumatic TMJ dislocation. The patients were grouped randomly. The supine position technique was applied in both N2O group (experimental group) and control group (without N2O). The visual analogue scale scores (VAS scores) of the pain perception and the operation time were recorded. RESULTS: All patients with dislocated mandible were successfully managed. The VAS scores of pain perception were significantly reduced in N2O group. It was 1.63 compared to 4.00 in control group. The average operation time was also significantly reduced in N2O group (Supplemental Digital Content, Table 2, http://links.lww.com/SCS/A716). It was 129.92 seconds compared to 170.04 seconds in control group. CONCLUSION: Inhalation of N2O helps to reduce the pain perception and the operation time of manual reduction of acute nontraumatic TMJ dislocation using the supine position technique. It is beneficial to both patients and doctors.

Leptin induces IL-6 and IL-8 expression through leptin receptor Ob-Rb in human dental pulp fibroblasts.

OBJECTIVE: Leptin, through binding to its special receptor (Ob-Rb), has potent effects on immunity and inflammation. This study aimed to investigate the expression of leptin receptor Ob-Rb in human dental pulp fibroblasts (HDPFs) and the effects of leptin on the production of proinflammatory cytokines of IL-6 and IL-8 by HDPFs. METHODS: Ob-Rb expression was determined by quantitative real-time PCR (real-time PCR), Western blot and immunofluorescence analyses in cultured HDPFs. Small interfering RNA (siRNA) was transfected into HDPFs to down-regulate the expression of Ob-Rb. Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were used to determine the proinflammatory cytokines of IL-6 and IL-8 levels in leptin-stimulated HDPFs. The involved signalling pathways that mediate the leptin-stimulated production of proinflammatory cytokines were investigated using Western blot and specific signalling inhibitor analyses. RESULTS: The expression levels of Ob-Rb mRNA and protein were detected in HDPFs. Leptin could stimulate mRNA and protein expression of IL-6 and IL-8 in HDPFs in a concentration-dependent and time-dependent manner. Transfection with siRNA targeting Ob-Rb resulted in remarkable reduction of IL-6 and IL-8 expressions by HDPFs. In accordance with the enhanced expression of proinflammatory cytokines, leptin stimulation resulted in rapid phosphorylation of STAT3, p38 MAPK, ERK and Akt in HDPFs. Inhibiting JAK2/STAT3, p38 MAPK or PI3K/Akt substantially decreased leptin-induced IL-6 production, whereas blocking ERK and p38 MAPK substantially suppressed IL-8 production from leptin-stimulated HDPFs. CONCLUSIONS: Leptin may up-regulate IL-6 and IL-8 production through binding with Ob-Rb in HDPFs via the activation of different intracellular signalling pathways.

Early predictors of responses and clinical outcomes of corticosteroid treatment for severe ulcerative colitis.

BACKGROUND: Patients with severe ulcerative colitis (SUC) have a high risk of requiring colectomy or resorting to a second-line treatment. However, neither clinical outcomes nor factors predictive of poor response have been clearly established in the treatment of SUC. OBJECTIVE: To assess prospectively the effects and predictors of corticosteroids (CS) use in clinical outcomes of SUC during 1 year of follow-up. MATERIAL AND METHODS: Consecutive inpatients with SUC, who had been treated with intravenous CS, were enrolled. Patients were monitored by clinical, laboratory, and endoscopic examinations, and the data were recorded for 1 year. Univariate and multivariate analyses were performed at 1 week. RESULTS: There were 22.6% (14/62) nonresponders at 7 days. Several predictors were associated with nonresponse to CS. These included Mayo Score at baseline (p = 0.007), partial Mayo Score, number of bowel movements, blood presence in stool, abdominal pain, and levels of C-reactive protein (CRP), hemoglobin (Hgb), platelet count (PLT), and erythrocyte sedimentation rate (ESR) on day 3 (p < 0.05). Multiple logistic regression analysis identified the Partial Mayo Score at day 3 as an independent predictor of outcome (p = 0.012). A total of 12 patients underwent colectomy within 1 year. The short-term response rates to intravenous cyclosporin (CsA) and infliximab (IFX) in SUC were 71.4% (5/7) and 77.8% (7/9), respectively. CONCLUSIONS: Many patients with SUC eventually became refractory to or dependent on CS. The Mayo score and laboratory characteristics were factors useful in predicting short-term outcome of CS treatment. Secondary medical therapy can help avoid emergency surgery.

Advanced prostate cancer diagnosed by bone metastasis biopsy immediately after initial negative prostate biopsy: a case report and literature review.

Prostate cancer (PCa) is a prevalent male malignancy that originates in the epithelial cells of the prostate. In terms of incidence and mortality of malignant tumors in men, PCa ranks second and fifth globally and first and third among men in Europe and the United States, respectively. These figures have gradually increased in recent years. The primary modalities used to diagnose PCa include prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI), and prostate puncture biopsy. Among these techniques, prostate puncture biopsy is considered the gold standard for the diagnosis of PCa; however, this method carries the potential for missed diagnoses. The preoperative evaluation of the patient in this study suggested advanced PCa. However, the initial prostate puncture biopsy was inconsistent with the preoperative diagnosis, and instead of waiting for a repeat puncture of the prostate primary, we performed a biopsy of the rib metastasis, which was later diagnosed as advanced PCa.

Renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion: A case report and literature review.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion is a rare subtype of RCC. A 31-year-old male patient was admitted to The Affiliated Hospital of Zunyi Medical University (Zunyi, China) with a solid mass in the left kidney during a routine health examination. After ruling out surgical contraindications, the patient underwent a laparoscopic left partial nephrectomy under general anesthesia. Postoperative pathology and fluorescence in situ hybridization (FISH) identified Xp11.2 translocation RCC. There was no tumor recurrence or metastasis during the 1-year follow-up. Xp11.2 translocation RCC is unusual, its clinical and imaging findings are not specific, and the diagnosis depends on TFE3-immunohistochemical assay and FISH analysis. Surgical resection is the first choice of treatment and its prognosis is worse than that of clear cell RCC, thus regular follow-ups are necessary.

Comparison of neoadjuvant chemotherapy response and prognosis between HR-low/HER2-negative BC and TNBC: an exploratory real-world multicentre cohort study.

Objective: Hormone receptor (HR)-low/HER2-negative breast cancers (BCs) are more likely to be basal-like BCs, with similar molecular features and gene expression profiles to HR-negative (estrogen receptor <1% or negative and progesterone receptor <1% or negative) BCs. Recently, with the clinical application of adjuvant intensive therapy for triple-negative breast cancer (TNBC), the prognosis of TNBC patients without pathological complete response (pCR) has significantly improved. Therefore, it is necessary to reanalyse the prognostic characteristics of clinically high-risk HR-low/HER2-negative BC. Methods: According to the inclusion and exclusion standards, 288 patients with HR-low/HER2-negative BC and TNBC who received NAC and were followed up between 2015 and 2022 at three breast centres in Hunan Province, China, were enrolled. Inverse probability of treatment weighting (IPTW) was utilized to mitigate imbalances in baseline characteristics between the HR-low/HER2-negative BC group and TNBC group regarding event-free survival (EFS) and overall survival (OS). The primary clinical endpoints were pCR and EFS, while the secondary endpoints included OS, objective response rate (ORR), and clinical benefit rate (CBR). Results: The pCR rate (27.1% vs. 28.0%, P = 1.000), ORR rate (76.9% vs. 78.3%, P = 0.827) and CBR rate (89.7% vs. 96.5%, P = 0.113) after NAC were similar between the HR-low/HER2-negative BC and the TNBC group. EFS in patients with non-pCR from the 2 groups was significantly inferior in comparison to patients with pCR (P = 0.001), and the 3-year EFS was 94.74% (95% CI = 85.21% to 100.00%) and 57.39% (95% CI =43.81% to 75.19%) in patients with pCR and non-pCR from the HR-low/HER2-negative BC group, respectively, and 89.70% (95% CI = 82.20% to 97.90%) and 69.73% (95% CI = 62.51% to 77.77%) in the TNBC patients with pCR and non-pCR, respectively. Conclusions: In the real world, the therapeutic effects of NAC for HR-low/HER2-negative BCs and TNBCs were similar. EFS of patients with non-pCR in the HR-low/HER2-negative BC group was inferior to that of the TNBC group with non-pCR, suggesting that it is necessary to explore new adjuvant intensive therapy strategies for these patients.

Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.

A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

Nerve cells, or neurons, are the key communication components of the body. Each neuron takes signals from many inputs and transmits them through a single output called the axon. In the central nervous system, which consists of the brain and spinal cord, damaged neurons do not generally repair themselves. But in the peripheral nervous system, where neurons branch out to other parts of the body, they can regenerate. For this to happen, genes which promote axon regrowth must be expressed. Messenger RNA carries DNA information from the nucleus of a cell to the cytoplasm where it serves as instructions for generating proteins. Certain enzymes can modify messenger RNA, changing how long it lasts, where it goes in the cell and what proteins it makes. It has been suggested that a particular RNA modification, known as m⁶A, plays an important role in axon regrowth as increased m⁶A levels have been reported in some neurons after a peripheral nerve injury. Wang et al. studied the impact of m⁶A modifications on axon regrowth by examining the effects of several genes associated with these modifications in rats. The experiments showed that expression of a gene called Alkbh5 ­ which codes for an enzyme that removes m⁶A modifications ­ regulates the amount of axon regrowth following an injury to peripheral nerves. Reducing the amount of Alkbh5 expression rates increased axon regrowth, whereas in rats where Alkbh5 was overexpressed, regrowth was reduced. Further experiments showed that the ALKBH5 enzyme helps to make mRNA from the gene Lpin2 more stable, which affects how it processes fats and lipids during the regeneration process. Moreover, in the central nervous system, reducing Alkbh5 expression enhanced survival and axon regrowth of neurons in the eye after they were injured in mice. The findings suggest that Alkbh5 influences axon regrowth and are an important step towards understanding how biological systems repair nerve damage. Future work should investigate if stopping Alkbh5 expression allows injured neurons to recover their function and how different m⁶A-associated enzymes work together in this process.

Treatment of Pulp Canal Obliteration Using a Dynamic Navigation System: Two Case Reports.

Endodontic treatment of calcified canals presents a major challenge because of the high incidence of complications, such as perforation, canal geometry alteration, and loss of dental hard tissue. The dynamic navigation technique uses an optical tracking system for real-time navigation to guide the operator to drill according to the preoperative plan and obtain access to the calcified canals. This article describes in detail the use, advantages, disadvantages, and limitations of a novel dynamic navigation system in 2 cases with severely calcified canals. The findings in these cases demonstrate that dynamic navigation system is a promising technique for locating calcified root canals.

Efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy regimen in Chinese patients with HER2-positive early breast cancer: a real-world retrospective multi-center cohort study.

Background: Pertuzumab plus trastuzumab combined with chemotherapy has become a standard neoadjuvant therapy option for patients with high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). There is still not enough evidence for the efficacy and safety of neoadjuvant pertuzumab and trastuzumab plus chemotherapy in HER2-positive BC patients in China, both in clinical trials and real-world settings. This study aimed to assess the efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive BC in real-world clinical application. Methods: We retrospectively collected the data from the electronic medical records of HER2-positive patients treated with neoadjuvant trastuzumab and pertuzumab plus chemotherapy from December 2018 to May 2021 at 21 hospitals located in Hunan Province, China, including age, American Joint Committee on Cancer (AJCC) stage, clinical tumor size, clinical lymph node status, pathological characteristics (before neoadjuvant systemic therapy), treatment approach, adverse events to neoadjuvant therapy, and achievement of pathological complete response (pCR). The primary endpoint was the total rate of pCR, and the secondary endpoints were the rate of pCR of each subgroup and the safety of dual anti-HER2 therapy. Results: A total of 188 patients met the inclusion criteria and were included in the analysis. Of the 188 patients, 119 (63.3%) were diagnosed at stage II and 64 (34.0%) at stage III; 163 (86.7%) were cT2-3; 149 patients (79.3%) were ≥ cN1; 84 patients (44.7%) were hormone receptor (HR)-positive. pCR was observed in 88 of 188 patients (46.8%). The pCR rate of HR-negative patients (54.8%) was higher (P=0.014) than that of HR-positive patients (36.9%). Patients with Ki-67 <15% achieved a higher (P=0.033) pCR rate (68.2%) than those with Ki-67 ≥15% (44.0%). Anemia was the most common adverse event (63.4%), and the most common grade 3-4 adverse event was nausea and vomiting (8.5%). Conclusions: Our study confirmed the benefit of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy on pCR with a tolerable safety profile in routine clinical practice in Chinese patients with HER2-positive BC. HR-negativity and Ki-67 <15% were associated with pCR in these patients.

Comparison of Needle, Ultrasonic, and Laser Irrigation for the Removal of Calcium Hydroxide from Mandibular Molar Root Canals.

Objective: This study aimed to compare the efficacy of conventional needle irrigation (CI), ultrasonically activated irrigation (UAI), photon-induced photoacoustic streaming (PIPS), and shock wave-enhanced emission photoacoustic streaming (SWEEPS) in removing calcium hydroxide [Ca(OH)2] from root canals of mandibular molars using microcomputed tomography. Background: Various adjunctive irrigation strategies have been recommended to improve the removal of Ca(OH)2. No reports have evaluated the SWEEPS laser-activated method for the removal of Ca(OH)2 from root canals of mandibular molars. Materials and methods: Forty mandibular molars were instrumented and filled with Ca(OH)2. Four irrigation groups (CI, UAI, PIPS, and SWEEPS) were established. The volume of root canals and Ca(OH)2 and the Ca(OH)2 volume reduction percentage (%Rd) were calculated. Data were analyzed by one-way analysis of variance and Kruskal-Wallis analysis of variance. Results: The residual Ca(OH)2 in the apical third was higher than that in the cervical and middle thirds in all groups (p < 0.05). Comparison of the %Rd of Ca(OH)2 in mesial canals revealed that PIPS and SWEEPS removed more Ca(OH)2 than CI and UAI in the cervical third (p < 0.05). The middle third of the mesial canals and the cervical and middle thirds of the distal canals did not show significant differences among groups (p > 0.05). Significant differences in the %Rd of Ca(OH)2 were noted between CI and other groups in the apical third of mesial and distal canals (p < 0.05). No group demonstrated complete removal of Ca(OH)2. Conclusions: UAI and laser-activated irrigation significantly improved Ca(OH)2 removal in the apical third of mesial and distal canals. No agitation technique could completely remove Ca(OH)2.

Klf2-Vav1-Rac1 axis promotes axon regeneration after peripheral nerve injury.

Increasing the intrinsic regeneration potential of neurons is the key to promote axon regeneration and repair of nerve injury. Therefore, identifying the molecular switches that respond to nerve injury may play critical role in improving intrinsic regeneration ability. The mechanisms by which injury unlocks the intrinsic axonal growth competence of mature neurons are not well understood. The present study identified the key regulatory genes after sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found that the hub gene Vav1 was highly expressed at both early response and regenerative stages of sciatic nerve injury. Furthermore, Vav1 was required for axon regeneration of dorsal root ganglia (DRG) neurons and functional recovery. Krüppel-like factor 2 (Klf2) was induced by retrograde Ca2+ signaling from injured axons and could directly promote Vav1 transcription in adult DRG neurons. The increased Vav1 then promoted axon regeneration by activating Rac1 GTPase independent of its tyrosine phosphorylation. Collectively, these findings break through previous limited cognition of Vav1, and first reveal a crucial role of Vav1 as a molecular switch in response to axonal injury for promoting axon regeneration, which might further serve as a novel molecular therapeutic target for clinical nerve injury repair.

Corrigendum: Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis.

[This corrects the article DOI: 10.3389/fonc.2020.00811.].

Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data.

PURPOSE: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. EXPERIMENTAL DESIGN: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. RESULTS: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). CONCLUSIONS: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity. Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed. Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3-4 AEs. Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.

Positive Correlation between Activated CypA/CD147 Signaling and MMP-9 Expression in Mice Inflammatory Periapical Lesion.

AIM: Cyclophilin A (CypA)/CD147 signaling plays critical roles in the regulation of inflammation and bone metabolism. This study aimed to investigate the participation of CypA/CD147 in mice periapical lesions progression and its relationship with bone resorption. METHODOLOGY: Periapical lesions were induced by pulp exposure in the first lower molars of 40 C57BL/6J mice. The mice were sacrificed on days 0, 7, 14, 21, 28, 35, 42, and 49. Mandibles were harvested for X-ray imaging, microcomputed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. Western blot was employed to further detect the related molecular signaling pathways in LPS-stimulated RAW 264.7 cells treated with CypA inhibitor. RESULTS: The volume and area of the periapical lesions increased from day 0 to day 35 and remained comparably stable until day 49. Immunohistochemistry demonstrated that the CypA expression levels also increased from day 0 to day 35 and decreased until day 49, similar to CD147 expression (R 2 = 0.4423, P < 0.05), osteoclast number (R 2 = 0.5101, P < 0.01), and the expression of osteoclastogenesis-related matrix metalloproteinase 9 (MMP-9) (R 2 = 0.4715, P < 0.05). Serial sections further confirmed the colocalization of CypA and CD147 on osteoclasts with immunohistochemistry. And the distribution of CypA-positive or CD147-positive cells was positively correlated with the dynamics of MMP-9-positive cells by using immunofluorescence analysis. Furthermore, CD147 and MMP-9 expression in RAW 264.7 cells were both downregulated with CypA inhibitor treatment (P < 0.05). CONCLUSIONS: The present study reveals the positive correlation of CypA/CD147 signaling and osteoclast-related MMP-9 expression in mice inflammatory periapical lesions progression. Therefore, intervention of CypA/CD147 signaling could probably provide a potential therapeutic target for attenuating inflammatory bone resorption.