PD-L1-expressing tumor-associated macrophages are immunostimulatory and associate with good clinical outcome in human breast cancer.

Tumor-associated macrophages (TAMs) are the predominant cells that express programmed cell death ligand 1 (PD-L1) within human tumors in addition to cancer cells, and PD-L1+ TAMs are generally thought to be immunosuppressive within the tumor immune microenvironment (TIME). Using single-cell transcriptomic and spatial multiplex immunofluorescence analyses, we show that PD-L1+ TAMs are mature and immunostimulatory with spatial preference to T cells. In contrast, PD-L1- TAMs are immunosuppressive and spatially co-localize with cancer cells. Either higher density of PD-L1+ TAMs alone or ratio of PD-L1+/PD-L1- TAMs correlate with favorable clinical outcome in two independent cohorts of patients with breast cancer. Mechanistically, we show that PD-L1 is upregulated during the monocyte-to-macrophage maturation and differentiation process and does not require external IFN-γ stimulus. Functionally, PD-L1+ TAMs are more mature/activated and promote CD8+ T cells proliferation and cytotoxic capacity. Together, our findings reveal insights into the immunological significance of PD-L1 within the TIME.

Open Versus Arthroscopic Latarjet for Recurrent Anterior Shoulder Instability: A Systematic Review and Meta-analysis.

Background: The open Latarjet (OL) procedure and arthroscopic Latarjet (AL) procedure are able to treat recurrent anterior shoulder instability (RASI) with high success rates. Purpose: To evaluate the clinical efficacy and postoperative revisions and complications between the OL and AL procedures in the treatment of RASI. Study Design: Systematic review; Level of evidence, 3. Methods: MEDLINE, Embase, and the Cochrane Library were searched to retrieve and include cohort studies comparing the OL and AL procedures for RASI. Clinical outcomes were compared, and results were reported as odds ratios (ORs) or mean differences (MDs) with 95% CIs. Results: Eleven clinical trials with 1217 patients were included. There were no differences between the procedures in pain score, Rowe score, Walch-Duplay score, external rotation, persistent apprehension, instability, recurrence, revisions attributed to recurrent instability, overall complications, wound infection, hematoma, graft complications, screw-related complications, or osteoarthritis. When compared with the OL procedure, the AL procedure had a significantly lower nonunion rate (OR, 9.92; 95% CI, 1.71 to 57.71; P = .01); however, the AL procedure had a longer operation time (MD, -24.49; 95% CI, -48.44 to -0.54; P = .05), lower Western Ontario Shoulder Instability Index score (MD, 97.27; 95% CI, 21.91 to 172.63; P = .01), higher revision rate (OR, 0.39; 95% CI, 0.16 to 0.95; P = .04), and greater screw deviation (MD, -6.41; 95% CI, -10.25 to -2.57; P = .001). Conclusion: For most outcome measures, no difference was seen between the OL and AL procedures. The AL procedure had a lower Western Ontario Shoulder Instability Index score and a higher revision rate and appeared to have a significant learning curve. However, the AL procedure resulted in a lower nonunion rate.

The transmission pattern and clinical course of the first 417 patients with COVID-19 infection in Shenzhen, China.

OBJECTIVE: To explore the transmission patterns and clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first identified in Wuhan, China in December 2019 as clustered and non-clustered cases of coronavirus disease (COVID-19) emerged in Shenzhen, China. METHODS: This retrospective study included the patients that were confirmed by laboratory detection of SARS-CoV-2 in Shenzen between 19 January 2020 and 21 February 2020. Data on the epidemiological and clinical characteristics were analysed. The patients were divided into non-clustered and clustered groups. The time course, intervals between first and second COVID-19 cases and other transmission patterns were compared between the groups. RESULTS: The 417 patients were divided into clustered (n = 235) and non-clustered groups (n = 182). Compared with the non-clustered group, the clustered group had significantly more young (≤20 years) and old (>60 years) patients. The clustered group had significantly more severe cases (nine of 235; 3.83%) compared with the non-clustered group (three of 182; 1.65%). Patients with severe disease spent 4-5 more days of hospitalization than patients with moderate and mild disease. CONCLUSION: This retrospective study analysed the transmission patterns and clinical course of the first wave of COVID-19 infection in Shenzhen, China.

Predictive and Prognostic Value of TRIM58 Protein Expression in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

Introduction: Tripartite motif-containing protein (TRIM) family members play crucial roles in carcinogenesis and chemotherapy resistance. In this study, we aimed to determine whether TRIM58 protein expression is related to patient responses to neoadjuvant therapy (NAT) and their survival outcome. Methods: Immunohistochemistry was performed on female breast cancer samples from biopsies before NAT in Shenzhen Second People's Hospital. Univariate and multivariate logistic regression tests were used to analyze the association between TRIM58 protein expression and pathological complete response (pCR). The Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with a 95% confidence interval (95% CI). The Kaplan-Meier plotter database was used to analyze the prognostic value of TRIM58. Results: High TRIM58 expression was associated with small tumor size in all the patients (n = 58). Multivariate analysis suggested that low TRIM58 expression was an independent predictive factor for higher pCR (odds ratio = 0.06, 95% CI 0.005-0.741, P = 0.028). The Kaplan-Meier Plotter dataset suggested that the TRIM58 high-expression group showed a worse 5-year overall survival than the low-expression group (HR = 1.34, 95% CI 1.07-1.67, P = 0.01). Pathway analysis revealed the potential mechanisms of TRIM58 in chemoresistance. Discussion: Our study suggests that TRIM58 is a promising biomarker for both neoadjuvant chemosensitivity and long-term clinical outcomes in breast cancer. It may also help to identify candidate responders and determine treatment strategies.

Determining prognostic factors and optimal surgical intervention for early-onset triple-negative breast cancer.

Background: Few studies have focused specifically on prognostic factors and optimal surgical intervention for early-onset triple-negative breast cancer (eTNBC), which is characterized by high malignancy and poor prognosis. Methods: We performed a cohort study with a median follow-up of 31 months using Surveillance, Epidemiology, and End Results (SEER) data of patients diagnosed with stages I-III eTNBC between 2010 and 2016. In addition, we collected cases between 2006 and 2016 from our center as an external validation set. Clinical features, pathologic characteristics and oncologic outcomes were analyzed. Prognostic factors for overall survival (OS) and breast cancer-specific survival (BCSS) were determined by Cox proportional hazards analyses and were incorporated into the prognostic nomogram. Subgroup analysis based on propensity score matching method was conducted to explore the subset of patients that would benefit from breast-conserving therapy (BCT). Results: Based on SEER dataset, patients with eTNBC were more likely to undergo mastectomy than BCT. On multivariable analysis, patients with better survival outcomes were those not married, uninsured, had higher T and N stage, and had histological type of mixed invasive ductal and lobular carcinoma. The prognostic nomogram based on these variables successfully predicted the 3- and 5-year BCSS (C-index in training cohort, 0.774; in validation cohort from SEER, 0.768; in validation cohort from our center, 0.723). Subgroup analysis illustrated that patients with T1N0M0 or T2-4N+M0 tumors who underwent BCT achieved longer overall survival than those who underwent mastectomy (for T1N0M0, P = 0.022; for T2-4N+M0, P = 0.003); however, the type of surgery did not influence OS among patients with T1N+M0 or T2-4N0M0 tumors (for T1N+M0, P = 0.305; for T2-4N0M0, P = 0.317). Conclusions: The prognosis of patients with eTNBC is mainly affected by marital status, insurance status, T stage, N stage and histological type. The prognostic nomogram based on these factors is quite reliable. Subgroup analysis suggested that BCT may be a superior option for patients with eTNBC, especially those with T1N0M0 and T2-4N+M0 tumors.

The miR-548d-5p/SP1 signaling axis regulates chondrocyte proliferation and inflammatory responses in osteoarthritis.

Chondrocyte apoptosis and dysfunction play an important role in osteoarthritis (OA), a chronic progressive arthropathy. Non-coding RNAs have been implicated in OA pathogenesis. In this study, microRNA (miR)-548d-5p was found to be downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p overexpression partially reversed IL-1ß-induced chondrocyte damage in vitro, evidenced by the promotion of cell growth, the inhibition of apoptosis and inflammatory cytokine release, and the improvement in extracellular matrix (ECM) deposition. Furthermore, miR-548d-5p overexpression partially reversed papain-induced damages on OA rat's knee articular cartilage. Specificity protein 1 (SP1) was inhibited by miR-548d-5p and identified as its direct downstream target. In IL-1ß-stimulated chondrocytes, SP1 overexpression significantly attenuated the protective effects of miR-548d-5p overexpression against chondrocyte damage. In conclusion, miR-548d-5p was abnormally downregulated in OA samples and IL-1ß-stimulated chondrocytes. miR-548d-5p protects against IL-1ß-induced chondrocyte damage via direct inhibition of SP1.

Arthroscopic reconstruction of anterior cruciate ligaments with allograft: single-tunnel single-bundle versus single-tunnel double-bundle techniques.

PURPOSE: To compare the clinical results of anterior cruciate ligament (ACL) reconstruction using the single-tunnel single-bundle (STSB) technique versus the single-tunnel double-bundle (STDB) technique. METHODS: This was a retrospective, single-center, single-surgeon study based on data collected from March 2012 to June 2013. According to our inclusion/exclusion criteria, a total of 78 patients (64 males, 14 females; mean age, 25.1 years) who underwent arthroscopic ACL reconstruction with anterior tibialis tendon allografts through either the STSB technique (36 cases) or the STDB technique (42 cases) in our department were recruited. The International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores were used to evaluate the subjective function of the knee joint during the postoperative follow-up. The Lachman test and pivot shift test were used to objectively assess the stability of the knee. RESULTS: The average follow-up duration was 24.9 ± 1.8 months in the STSB group and 24.6 ± 1.7 months in the STDB group (P > 0.05). Patients in both groups recovered to the preoperative sports level with few complications. The postoperative Lysholm score (86.1 ± 7.5 vs. 47.7 ± 9.0 in the STSB group; 87.0 ± 7.1 vs. 48.2 ± 8.3 in the STDB group), IKDC score (87.8 ± 7.2 vs. 49.3 ± 6.1 in the STSB group; 88.7 ± 6.6 vs. 49.8 ± 6.3 in the STDB group), Tegner score (6.5 ± 1.3 vs. 2.5 ± 1.3 in the STSB group; 6.6 ± 1.2 vs. 2.6 ± 1.2 in the STDB group), Lachman test positive rate (8.3% vs. 89.9% in the STSB group; 7.1% vs. 85.7% in the STDB group), and pivot shift test positive rate (27.8% vs. 63.9% in the STSB group; 7.1% vs. 69.0% in the STDB group) were significantly improved compared to the preoperative status in both groups (P < 0.05). However, no statistically significant difference was observed between the two groups at the final follow-up (P > 0.05), except for the pivot shift test positive rate in the STDB group versus the STSB group (7.1% vs. 27.8%, P < 0.05). CONCLUSIONS: The STDB technique achieved a satisfactory clinical outcome with better rotational stability compared to the traditional STSB technique and therefore provided an effective option for ACL reconstruction. LEVEL OF EVIDENCE: Case series, Level IV.

RNA binding protein POP7 regulates ILF3 mRNA stability and expression to promote breast cancer progression.

RNA binding proteins (RBPs) play pivotal roles in breast cancer (BC) development. As an RBP, Processing of precursor 7 (POP7) is one of the subunits of RNase P and RNase MRP, however, its exact function and mechanism in BC remain unknown. Here, we showed that expression of POP7 was frequently increased in BC cells and in primary breast tumors. Upregulated POP7 significantly promoted BC cell proliferation in vitro and primary tumor growth in vivo. POP7 also increased cell migration, invasion in vitro, and lung metastasis in vivo. Through RNA immunoprecipitation coupled with sequencing (RIP-seq), we found that POP7 bound preferentially to intron regions and POP7-binding peak associated genes were mainly enriched in cancer-related pathways. Furthermore, POP7 regulated Interleukin Enhancer Binding Factor 3 (ILF3) expression through influencing its mRNA stability. Knockdown of ILF3 significantly impaired the increased malignant potential of POP7-overexpressing cells, suggesting that POP7 enhances BC progression through regulating ILF3 expression. Collectively, our findings provide the first evidence for the important role of POP7 and its regulation of ILF3 in promoting BC progression.

Single tunnel technique versus coracoid sling technique for arthroscopic treatment of acute acromioclavicular joint dislocation.

To evaluate and compare the efficacy of two techniques for the treatment of acute acromioclavicular joint dislocation, the charts of 60 patients diagnosed with acute Rockwood type IV and V acromioclavicular joint dislocation that undergone arthroscopic fixation procedure with single tunnel technique (N = 30, 30.7 ± 5.7 years old) or coracoid sling technique (N = 30, 30.1 ± 5.4 years old) fixation were retrospectively reviewed. The Visual Analog Scale pain score, Constant shoulder functionality score, Karlsson acromioclavicular joint score, the time of return to sports and activity, and plain radiographs of the affected shoulder at different time points of follow-up were recorded for a minimum of 2 years post-op. The majority of the patients recovered to their preoperative activity levels with few complications. The average postoperative acromioclavicular and coracoclavicular distances were significantly narrower than preoperative measurements in both groups without significant difference between the two groups at 2 years post-op (P < 0.05). The coracoid sling technique group had reduced operative time, shorter time of recovery of shoulder movements, higher Constant functionality scores and Karlsson acromioclavicular joint scores, and fewer complications than the single tunnel technique group at the last follow-up (P < 0.05). Therefore, coracoid sling technique achieved superior clinical outcomes with fewer complications compared to the traditional single tunnel technique in arthroscopic treatment of acute acromioclavicular joint dislocation.

Prognostic Factors and a Nomogram Predicting Survival in Patients with Breast Ductal Carcinoma in situ with Microinvasion: A Population-Based Study.

PURPOSE: Ductal carcinoma in situ with microinvasion (DCISM) can be challenging to balance the risks of overtreatment versus undertreatment. We aim to identify prognostic factors in patients with DCISM and construct a nomogram to predict breast cancer-specific survival (BCSS). MATERIALS AND METHODS: A retrospective cohort study of women diagnosed with DCISM from 1988 to 2015 who were identified in the Surveillance, Epidemiology and End Results database. Clinical variables and tumor characteristics were evaluated, and Cox proportional-hazards regression was performed. A nomogram was constructed from the multivariate logistic regression to combine all the prognostic factors to predict the prognosis of DCISM patients at 5 years, 10 years, and 15 years. RESULTS: We identified 5438 total eligible breast cancer patients with a median and max survival time of 78 and 227 months, respectively. Here, patients with poorer survival outcomes were those diagnosed between 1988 and 2001, African-American race, under 40 years of age, higher tumor N stage, progesterone receptor-negative tumor, and received no surgery. The nomogram was constructed by the seven variables and passed the calibration and validation steps. The area under the receiver operating characteristic (ROC) curve (AUC) of both the training set and the validating set (5-year AUC: 0.77 and 0.88, 10-year AUC: 0.75 and 0.73, 15-year AUC: 0.72 and 0.65). Receiving chemotherapy was associated with a better BCSS (hazard ratio, HR=0.45, 95% confidence interval, 95% CI = 0.23-0.89), especially in patients with estrogen receptor (ER) negative, progesterone receptor (PR) negative (HR = 0.35, 95% CI = 0.13-0.97) and ER+PR-/ER-PR+ DCISM (HR = 0.07, 95% CI = 0.01-0.59). CONCLUSION: Our current study is the first to construct nomograms of patients with DCISM which could help physicians identify breast cancer patients that more likely to benefit from more intensive treatment and follow-up. Chemotherapy might benefit patients with ER-PR- and ER+PR-/ER-PR+ DCISM.

Arthroscopic acetabular labrum reconstruction with capsular autograft: clinical outcome and preliminary results.

To introduce a novel technique to reconstruct the acetabular labrum using capsular autograft, and to evaluate the preliminary clinical outcome, a retrospective review of a prospectively collected registry was undertaken that identified 21 patients (21 hips) who underwent arthroscopic reconstruction of the labrum by capsular autograft from January 2016 to January 2018. Modified Harris Hip Score (mHHS), Hip Outcome Score (HOS), and Hip Outcome Score-Activities of Daily Living (HOS-ADL) were recorded preoperatively and postoperatively. Clinical outcome was analyzed to evaluate the effectiveness of this technique. Twenty-one patients, with an average follow-up time of 25.4 ± 1.6 months, were included in this study: 7 patients were diagnosed with hypoplastic labrum (width <5 mm), 9 patients with complex tear of labrum, and 5 patients with degenerative labrum. The mHHS (61.3 ± 5.5 vs. 87.5 ± 4.2, P<0.001), HOS (52.5 ± 5.1 vs. 87.3 ± 3.8, P<0.001) and HOS-ADL (48.5 ± 5.8% vs. 75.2 ± 3.5%, P<0.001) between preoperative and the 6-month follow-up were significantly different. Gender exerts no influence on the outcome of mHHS, HOS and HOS-ADL. Therefore, local capsular autograft is readily available during arthroscopy with no donor-site morbidity. The reconstruction of the hip labrum may be valuable for patients with hypoplastic or dysplastic labrum, complex tear of labrum and severe degeneration. With appropriate patient selection, this technique is promising in preliminary clinical outcome.

Protective Effect of SIRT1 Activator on the Knee With Osteoarthritis.

Osteoarthritis (OA), one of the most common chronic musculoskeletal disorders, is deemed to be correlated with aging. The SIRT1 activator, resveratrol, acts as a crucial regulator of aging and may have a potential therapeutic effect on OA. Rabbit OA models were established through destabilized medial meniscus surgery. A total of 40 healthy male New Zealand rabbits were divided into five groups: control group (sham operation), OA group, as well as low dose (LD), middle dose (MD), and high dose (HD) resveratrol-treated OA groups. 6 weeks after operation, 0.8 ml of normal saline was injected into the knee joints every other day in the control and OA groups, and 0.8 ml of 5, 10, and 15 µmol/L resveratrol was injected into the knee joints every other day in the LD, MD, and HD group, respectively. The rabbits were sacrificed 2 weeks after medication, and the articular cartilage of the knee joint was collected for Micro-CT, histology and Western blot analysis. Obvious articular cartilage lesion and joint space narrowing were detected in the OA group. Compared with the OA group, less osteoarthritic changes were observed in the MD and HD groups. The MD and HD groups had significantly lower bone volume fraction, trabecular number and Mankin scores than the LD and OA groups (p < 0.05). No significant difference was found between the OA and LD groups (p > 0.05). The expressions of SIRT1 and p53 detected by western blot were consistent with the aforementioned findings. Therefore, resveratrol can activate the SIRT1 gene to play a protective role in the OA process by inhibiting chondrocyte apoptosis, trabecular bone number increasing of the subchondral bone, as well as elevation of bone density. It demonstrated the importance of SIRT1 in maintaining articular cartilage health and provided a promising therapeutic intervention in the treatment of OA.

The Arthroscopic Application of Radiofrequency in Treatment of Articular Cartilage Lesions.

Articular cartilage lesion is a common disease to be treated by arthroscopic surgery. It will eventually progress to osteoarthritis without proper management, which can affect patients' work and daily life seriously. Although mechanical debridement and laser have been used clinically for its treatment, due to their respective drawbacks, radiofrequency has drawn increasing attention from clinicians as a new technique with more advantages. However, the safety and efficacy of radiofrequency have also been questioned. In this article, the scope of application of radiofrequency was reviewed following an introduction of its development history and mechanism, and the methods to ensure the safety and effectiveness of radiofrequency through power and temperature control were summarized.

Breast Cancer-Specific Mortality in Small-Sized Tumor with Stage IV Breast Cancer: A Population-Based Study.

BACKGROUND: Small-sized primary tumor does not always indicate a better prognosis. We hypothesized that very small primary breast tumors with extensive lymph node (LN) metastases represented an aggressive biologic behavior in stage IV disease. MATERIALS AND METHODS: Data between 2010 and 2015 were retrieved retrospectively from the Surveillance, Epidemiology, and End Results database with inclusion criteria of female sex, unilateral, metastatic, and T1/2 invasive ductal carcinoma. Primary study variables included T stage, N stage, grade, metastatic sites, number of involved sites, estrogen receptor status, progesterone receptor status, and human epidermal growth factor receptor 2 status. Kaplan-Meier and adjusted Cox proportional hazards models with interaction terms were used. One-, 2- and 3-year breast cancer-specific mortality (BCSM) was examined according to tumor size. RESULTS: We identified 5,340 eligible patients with breast cancer. In multivariate analysis, race, age, grade, molecular subtype, surgery, brain metastases, and liver metastases were found to be independently associated with BCSM. For T1 tumors, the N0, N1, and N2+ groups had the same BCSM. In tumors smaller than 50 mm, the 1-, 2-, and 3-year BCSM did not decline with the decrease of tumor size. For triple-negative breast cancers (TNBCs), the T1a/T1bN2+ group had significantly worse BCSM than any other group did. CONCLUSION: Patients with stage IV cancer with small-sized tumors may have BCSM as high as those with larger tumors. In TNBCs, very small tumors with severe LN involvement are associated with the worst BCSM. Continued efforts are needed to further investigate Ta1/T1bN2 + M1 TNBCs and individualize the treatment for affected patients. IMPLICATIONS FOR PRACTICE: This study revealed that for stage IV breast cancer, smaller primary tumors were not always associated with better breast cancer-specific mortality. This study illustrated that very small triple-negative breast cancers (TNBCs) with extensive regional lymph node involvement may be a surrogate for biologically aggressive disease. Because of poor prognosis of T1a/T1bN2+ TNBCs, there might be an urgent need of more individualized treatment for affected patients. Future correlative studies ought to focus on the genetic and molecular differences in Ta1/T1bN2+ TNBCs that contribute to the biological behavior. Clarification of the regulation mechanism of very small-sized primary TNBCs with metastatic outgrowth in nodes and distant sites will play an integral role in developing targeted therapies.

Truncated HDAC9 identified by integrated genome-wide screen as the key modulator for paclitaxel resistance in triple-negative breast cancer.

Rationale: Paclitaxel resistance is a major concern when treating triple-negative breast cancer (TNBC) patients. We aimed to identify candidates causing paclitaxel resistance and explore their significance in TNBC therapeutics. Methods: A genome-wide CRISPR screening, integrated with transcriptome analyses, was performed to identify candidates involved in paclitaxel-resistant TNBCs. Cell proliferation, cytotoxicity, immunofluorescent staining, and xenograft assays were conducted to verify the phenotypes of paclitaxel resistance induced by candidate genes, both in vitro and in vivo. RNA sequencing, Western blotting, and chromatin immunoprecipitation assays were used to explore the underlying mechanisms. Results: MEF2-interacting transcriptional repressor (MITR), the truncated isoform of histone deacetylase 9 (HDAC9) lacking the deacetylation domain, was enriched in paclitaxel-resistant cells. Elevated MITR expression resulted in increased interleukin-11 (IL11) expression and activation of downstream JAK/STAT3 signaling. Mechanistically, MITR counteracted MEF2A-induced transcriptional suppression of IL11, ultimately causing paclitaxel resistance. By contrast, pharmacological inhibition of JAK1/2 by ruxolitinib reversed paclitaxel resistance both in vitro and in vivo. Conclusion: Our in vitro and in vivo genetic and cellular analyses elucidated the pivotal role of MITR/MEF2A/IL11 axis in paclitaxel resistance and provided a novel therapeutic strategy for TNBC patients to overcome poor chemotherapy responses.

A retrospective study to compare the clinical effects of individualized anatomic single- and double-bundle anterior cruciate ligament reconstruction surgery.

To evaluate the clinical efficacy of single- and double- bundle individualized anatomic anterior cruciate ligament (ACL) reconstruction, we retrospectively analyzed the data and charts of 920 patients with ACL rupture who received individualized anatomic ACL reconstruction surgery at our center. All of the patients underwent arthroscopic ACL reconstruction with autologous hamstring tendons. The patients were divided into two groups: the single-bundle individualized anatomic reconstruction group (N = 539), and the double-bundle individualized anatomic reconstruction group (N = 381). The IKDC, Lysholm and Tegner scores were used to subjectively evaluate the function of the knee joint during the postoperative follow-up. The Lachman test, pivot shift test and KT-3000 were used to objectively evaluate the stability of the knee. All 920 patients participated in clinical follow-up (average duration: 27.91 ± 3.61 months) achieved satisfied outcomes with few complications. The postoperative IKDC, Lysholm and Tegner scores, and the objective evaluation of knee joint stability were significantly improved compared to the preoperative status in both groups (P < 0.05). No statistically significant difference was observed between the two groups at the final follow-up (P > 0.05). Therefore, no difference in terms of the IKDC, Lysholm and Tegner score, or KT-3000 was observed between the individualized anatomic single- and double-bundle ACL reconstruction techniques. Both techniques can be used to restore the stability and functionality of the knee joint with satisfactory short-term efficacy.

PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression.

Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. ©2018 AACR.

Androgen receptor expression predicts different clinical outcomes for breast cancer patients stratified by hormone receptor status.

In this study we sought to correlate androgen receptor (AR) expression with tumor progression and disease-free survival (DFS) in breast cancer patients. We investigated AR expression in 450 breast cancer patients. We found that breast cancers expressing the estrogen receptor (ER) are more likely to co-express AR compared to ER-negative cancers (56.0% versus 28.1%, P < 0.001). In addition, we found that AR expression is correlated with increased DFS in patients with luminal breast cancer (P < 0.001), and decreased DFS in TNBC (triple negative breast cancer, P = 0.014). In addition, patients with HR+ tumors (Hormone receptor positive tumors) expressing low levels of AR have the lowest DFS among all receptor combinations. We also propose a novel prognostic model using AR receptor status, BRCA1, and present data showing that our model is more predictive of disease free survival compared to the traditional TMN staging system.

The phosphorylation-specific association of STMN1 with GRP78 promotes breast cancer metastasis.

Metastasis is a major cause of death in patients with breast cancer. Stathmin1 (STMN1) is a phosphoprotein associated with cancer metastasis. It exhibits a complicated phosphorylation pattern in response to various extracellular signals, but its signaling mechanism is poorly understood. In this study, we report that phosphorylation of STMN1 at Ser25 and Ser38 is necessary to maintain cell migration capabilities and is associated with shorter disease-free survival (DFS) in breast cancer. In addition, we report that glucose-regulated protein of molecular mass 78 (GRP78) is a novel phospho-STMN1 binding protein upon STMN1 Ser25/Ser38 phosphorylation. This phosphorylation-dependent interaction is regulated by MEK kinase and is required for STMN1-GRP78 complex stability and STMN1-mediated migration. We also propose a prognostic model based on phospho-STMN1 and GRP78 to assess metastatic risk in breast cancer patients.