Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε.

Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis.

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the iron-sulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron-sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.

The impact of granulocyte colony-stimulating factor (G-CSF) on thin endometrium of an animal model with rats.

MATERIALS AND METHODS: After forming of the thin endometrium by uterine injection of 0.2 ml 96% ethyl alcohol to the rats, five days of subcutaneous injections of 40 µg/kg G-CSF or saline were given. Endometrial thickness, immunohistochemically expression of vascular endothelial growth factor receptor-2 (VEGF-R2), proliferative cell nuclear antigen (PCNA) and fibronectin apoptosis with TUNEL method were compared in specimens among four groups of post-model rats. RESULTS: Endometrial thickness was significantly improved in thin but not in normal endometrium group with GCSF when compared to saline injection. Stromal and glandular epithelial expression of PCNA and pericapillary VEGF-R2 was significantly increased, and apoptosis was significantly decreased with G-CSF. Although fibronectin was also increased with G-CSF in the thin endometrium, the difference was non-significant. In further, G-CSF decreased apoptotic cells and increased expression of PCNA when compared to saline injection in normal endometrium. CONCLUSIONS: G-CSF improves endometrial thickness, proliferation, angiogenesis and DNA fragmentation in thin endometrium.

Is the Southern Ocean getting greener?

The Southern Ocean is a key player in regulating the planet's biogeochemistry, productivity, and climate. Ocean color data from two NASA satellites show statistically significant increases in the concentration of chlorophyll in all sectors of the Southern Ocean, particularly in the Sub-Antarctic Zone and Permanently Open Ocean Zone. The smallest changes were observed in the Atlantic and Pacific sectors of the Sub-Tropical Zone. These trends seem accentuated by higher chlorophyll concentrations during the austral winter. Increases in the annual and wintertime chlorophyll concentrations can have implications for the Southern Ocean biological pump and ocean productivity and higher trophic levels. PLAIN LANGUAGE SUMMARY: The Southern Ocean is getting greener because the amount of marine plants (phytoplankton) has been increasing in the last 21 years. These changes appear to be happening faster during the winter, which suggests that the growing season is getting longer. This is important because the Southern Ocean has a big role in the biology and chemistry of the oceans, and in regulating the Earth's climate. This work was done using 21 years of data from two NASA satellites.

Comparison of patients with and without intellectual disability under general anesthesia: A retrospective study.

BACKGROUND AND PURPOSE: We analyzed and retrospectively compared patients with and without intellectual disability (ID) who underwent oral surgery under general anesthesia at Istanbul University, Faculty of Dentistry, Department of General Anesthesia, between October 2012 and June 2013 with regard to the following categories: Demographic features, American Society of Anesthesiologists (ASA) classification, Mallampati score, type of anesthetic drug used during the operation, type of intubation used, any difficulties with tracheal intubation, presence of systemic diseases, and recovery times after ending general anesthesia. MATERIALS AND METHODS: A total of 348 patients were selected from the Department of Maxillofacial Surgery and the Department of Pedodontics who underwent surgery with general anesthesia. Medical histories of all patients were taken, and their electrocardiography, chest X-rays, complete blood count, and blood clotting tests were checked during a preoperative assessment. Mallampati evaluations were also performed. Patients were grouped into ASA I, II, or III according to the ASA classification and were treated under general anesthesia. RESULTS: There was no significant difference between normal and intellectually disabled patients in terms of gender, Mallampati scores, intubation difficulties, mean anesthetic period, time to discharge, or postoperative nausea and vomiting. Epilepsy and genetic diseases in intellectually disabled patients were significantly more common than in non-ID (NID) patients. However, the frequency of diabetes and chronic obstructive pulmonary disease in NID patients was significantly higher than in the intellectually disabled patients. CONCLUSION: Dental treatment of intellectually disabled patients under general anesthesia can be performed just as safely as that with NID patients.

Is obesity associated with healing after non-surgical periodontal therapy? A local vs. systemic evaluation.

BACKGROUND: We aimed to detect the role of obesity on the healing response to periodontal therapy in terms of serum lipids, C-reactive protein (CRP) and both serum and gingival crevicular fluid adipocytokines. MATERIAL AND METHODS: Thirty patients with periodontitis with (CPO) (n = 15) and without (n = 15) obesity and 15 healthy controls were included. Serum high-density lipoprotein, low-density lipoprotein, triglyceride, CRP levels and levels of adiponectin, interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 were evaluated before and 3 mo after initial periodontal therapy. Clinical periodontal measurements were also recorded at baseline and 3 mo. RESULTS: Periodontal parameters improved significantly in both periodontitis groups with or without obesity (p < 0.05) with no significant difference in terms of gain clinical attachment level (p > 0.05) and change in numbers of sites with probing depth ≥ 4 mm. High-density lipoprotein significantly increased in both groups (p > 0.05). CRP decreased significantly solely in the normal weight group. IL-6, IL-10 and TNF-α levels in gingival crevicular fluid improved significantly based on therapy in both groups (p < 0.05). Only TNF-α decreased significantly in the CPO, while adiponectin and IL-10 in addition to TNF-α improved significantly in the group of patients with periodontitis without obesity. CONCLUSION: Patients with CPO respond to periodontal therapy as well as the non-obese controls. This similar response is accompanied with consistent adipokine levels in gingival crevicular fluid. However, obesity affects the CRP and serum adipocytokine levels in response to therapy.

Impact of testicular histopathology as a predictor of sperm retrieval and pregnancy outcome in patients with nonobstructive azoospermia: correlation with clinical and hormonal factors.

In this study, our objective was to evaluate the impact of testicular histopathology on the outcome of intracytoplasmic sperm injection (ICSI) cycles of patients with nonobstructive azoospermia and correlate with clinical and hormonal parameters. For this purpose, 271 patients with nonobstructive azospermia (NOA) who underwent testicular sperm extraction (TESE) for ICSI cycles were retrospectively evaluated for sperm retrieval, fertilisation, embryo cleavage, clinical pregnancy and live birth rates among different testicular histology groups. We also correlated hormonal and clinical factors with histological findings. Sperm retrieval and fertilisation rates (FR) were found to be significantly different among all testicular histological groups of NOA except for embryo cleavage, clinical pregnancy and live birth rates. Furthermore, serum follicle stimulating hormone (FSH) level was the most significant variable to predict sperm recovery on TESE. Separate analyses within each testicular histological group revealed that higher FSH was also associated with lower pregnancy rates in only maturation arrest group. In conclusion, testicular histology significantly influences sperm retrieval and FRs but not pregnancy and live birth rates in nonobstructive azoospermia. However, FSH is the best predictor of a successful TESE.

Activity of dental pulp cells in semisolid 3D cultures initiated by transforming growth factor-ß1 and bone morphogenetic protein 2, 4.

The intention of this study was to investigate the effect of modified 3D culture conditions on dental pulp cells (DPCs). DPCs were isolated from extracted primary molar, premolar, and wisdom teeth. Tooth samples were divided into three groups as control group; plated into methyl cellulose medium without any supplementation, growth factor (GF) group; supplemented with bone morphogenetic proteins (BMP2, BMP4), transforming growth factor—β1 (TGF—β1) and growth factor+conditioned medium (GF+CM) group; supplemented with both growth factors and pulp conditioned medium. The DPCs were tested for colony forming ability, proliferation capacity and morphology. The highest colony forming ability was detected in the GF and GF+CM groups of DPCs isolated from wisdom teeth. The proliferation capacity was higher in GF+CM group of DPCs isolated from primary molars, and in GF and GF+CM groups of DPCs isolated from wisdom teeth. Scanning electron microscope (SEM) observation of the wisdom teeth samples showed cell—cell interactions in the GF and GF+CM groups. Our results indicate that growth factors and pulp conditioned medium in methyl cellulose culture created proper environment to follow the behavior of dental cells three—dimensionally.

Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.

Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.

Henoch-Schönlein purpura without systemic involvement beginning with acute scrotum and mimicking torsion of testis.

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. Typical presentations of HSP are palpable purpura of the small vessels in the hips and lower limbs, abdominal pain, arthritis, and hematuria. Scrotal involvement manifested by the presence of scrotal pain and swelling during the course of the disease is rarely seen. HSP without systemic involvement with acute scrotum mimicking testicular torsion is even rare in the medical literature. In most cases, patients with this disease achieve complete recovery. Herein, we report an interesting HSP case with skin symptoms but without systemic involvement and then progression to acute scrotum resembling torsion of testis.

Ovarian stimulation strategies for intrauterine insemination in couples with unexplained infertility: a systematic review and individual participant data meta-analysis.

BACKGROUND: Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for unexplained infertility. Gonadotrophins, letrozole and clomiphene citrate (CC) are commonly used agents during IUI-OS and have been compared in multiple aggregate data meta-analyses, with substantial heterogeneity and no analysis on time-to-event outcomes. Individual participant data meta-analysis (IPD-MA) is considered the gold standard for evidence synthesis as it can offset inadequate reporting of individual studies by obtaining the IPD, and allows analyses on treatment-covariate interactions to identify couples who benefit most from a particular treatment. OBJECTIVE AND RATIONALE: We performed this IPD-MA to compare the effectiveness and safety of ovarian stimulation with gonadotrophins, letrozole and CC and to explore treatment-covariate interactions for important baseline characteristics in couples undergoing IUI. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO from their inception to 28 June 2021. We included randomized controlled trials (RCTs) comparing IUI-OS with gonadotrophins, letrozole and CC among couples with unexplained infertility. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA Collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Secondary outcomes were other reproductive outcomes, including time to conception leading to live birth. We performed a one-stage random effects IPD-MA. OUTCOMES: Seven of 22 (31.8%) eligible RCTs provided IPD of 2495 couples (62.4% of the 3997 couples participating in 22 RCTs), of which 2411 had unexplained infertility and were included in this IPD-MA. Six RCTs (n = 1511) compared gonadotrophins with CC, and one (n = 900) compared gonadotrophins, letrozole and CC. Moderate-certainty evidence showed that gonadotrophins increased the live birth rate compared to CC (6 RCTs, 2058 women, RR 1.30, 95% CI 1.12-1.51, I2 = 26%). Low-certainty evidence showed that gonadotrophins may also increase the multiple pregnancy rate compared to CC (6 RCTs, 2058 women, RR 2.17, 95% CI 1.33-3.54, I2 = 69%). Heterogeneity on multiple pregnancy could be explained by differences in gonadotrophin starting dose and choice of cancellation criteria. Post-hoc sensitivity analysis on RCTs with a low starting dose of gonadotrophins (≤75 IU) confirmed increased live birth rates compared to CC (5 RCTs, 1457 women, RR 1.26, 95% CI 1.05-1.51), but analysis on only RCTs with stricter cancellation criteria showed inconclusive evidence on live birth (4 RCTs, 1238 women, RR 1.15, 95% CI 0.94-1.41). For multiple pregnancy, both sensitivity analyses showed inconclusive findings between gonadotrophins and CC (RR 0.94, 95% CI 0.45-1.96; RR 0.81, 95% CI 0.32-2.03, respectively). Moderate certainty evidence showed that gonadotrophins reduced the time to conception leading to a live birth when compared to CC (6 RCTs, 2058 women, HR 1.37, 95% CI 1.15-1.63, I2 = 22%). No strong evidence on the treatment-covariate (female age, BMI or primary versus secondary infertility) interactions was found. WIDER IMPLICATIONS: In couples with unexplained infertility undergoing IUI-OS, gonadotrophins increased the chance of a live birth and reduced the time to conception compared to CC, at the cost of a higher multiple pregnancy rate, when not differentiating strategies on cancellation criteria or the starting dose. The treatment effects did not seem to differ in women of different age, BMI or primary versus secondary infertility. In a modern practice where a lower starting dose and stricter cancellation criteria are in place, effectiveness and safety of different agents seem both acceptable, and therefore intervention availability, cost and patients' preferences should factor in the clinical decision-making. As the evidence for comparisons to letrozole is based on one RCT providing IPD, further RCTs comparing letrozole and other interventions for unexplained infertility are needed.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5.

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5-mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich's ataxia.

Folic acid-conjugated polyethylene glycol-coated magnetic nanoparticles for doxorubicin delivery in cancer chemotherapy: Preparation, characterization and cytotoxicity on HeLa cell line.

Conventional chemotherapy is the most valid method to cope with cancer; however, it has serious drawbacks such as decrease in production of blood cells or inflammation of the lining of the digestive tract. These side effects occur since generally the drugs used in chemotherapy are distributed evenly within the body of the patient and cannot distinguish the cancer cells from the healthy ones. In this study, folic acid (FA)-conjugated, polyethylene-coated magnetic nanoparticles (FA-MNPs), and doxorubicin (Dox)-loaded formulation (Dox-FA-MNPs) were prepared. The cytotoxicity of these nanoparticles on HeLa and Dox-resistant HeLa cells was investigated. Magnetic nanoparticles (MNPs), polyethylene glycol (PEG)-coated MNPs (PEG-MNPs), and FA-MNPs were successfully synthesized and characterized by several methods. Dox loading of FA-MNPs and release profile of Dox from the nanoparticles were studied. Cytotoxic effects of FA-MNPs and Dox-FA-MNPs on HeLa cells were analyzed. MNPs, PEG-MNPs, and FA-MNPs all had small sizes and supermagnetic behavior. High amounts of Dox could be loded onto the nanoparticles (290 µgmL-1). In 24 h, 15.7% of Dox was released from the Dox-FA-MNPs. The release was increased in acidic conditions (pH 4.1). Internalization studies showed that FA-MNPs and Dox-FA-MNPs were taken up efficiently by HeLa cells. The investigation of cytotoxicity of the particles indicated that 38-500 µgmL-1 Dox-FA-MNPs significantly decreased the proliferation of HeLa cells compared to FA-MNPs. Due to their size, magnetic properties, internalization, drug release, and cytotoxicity characteristics, the MNPs prepared in this study may have potential application as a drug delivery system in cancer chemotherapy.

The impact of expectant management, systemic methotrexate and surgery on subsequent pregnancy outcomes in tubal ectopic pregnancy.

BACKGROUND: The most common treatment modalities of ectopic pregnancy may influence long-term subsequent fertility outcomes in women who previously treated for ectopic pregnancy. AIMS: Our objective was to compare long-term subsequent fertility outcomes after treatment with expectant management, systemic methotrexate (MTX) and surgery in tubal ectopic pregnancy. METHODS: We searched our database for all women diagnosed with tubal ectopic pregnancy between January 2007 and January 2011 who were managed expectantly, with systemic MTX and with surgery. Treatment success and spontaneous pregnancy rates were compared in patients who desire to conceive following a tubal pregnancy. RESULTS: One hundred twelve of 151 women desired to conceive following tubal ectopic pregnancy. Twenty-seven of 112 (24.1 %) patients were managed expectantly. Fifty-three (47.3 %) and 32 (28.5 %) patients were managed with systemic MTX or surgery, respectively. All patients in expectant and surgery groups were managed successfully. Two (3.7 %) patients had surgery after failed treatment with systemic MTX. Spontaneous intrauterine pregnancy rates were 62.9 % in expectantly managed women, 58.4 % in women with systemic MTX and 68.7 % in women with surgery (p > 0.05). CONCLUSIONS: Treatment of ectopic pregnancy with either expectant management or systemic MTX is equally effective as compared to surgery. Spontaneous intrauterine pregnancy rates were comparable in expectant management, systemic methotrexate and surgery.

An alternative method for the treatment of nonunion of the tibia with bone loss.

In this retrospective study we evaluated the method of acute shortening and distraction osteogenesis for the treatment of tibial nonunion with bone loss in 17 patients with a mean age of 36 years (10 to 58). The mean bone loss was 5.6 cm (3 to 10). In infected cases, we performed the treatment in two stages. The mean follow-up time was 43.5 months (24 to 96). The mean time in external fixation was 8.0 months (4 to 13) and the mean external fixator index was 1.4 months/cm (1.1 to 1.8). There was no recurrence of infection. The bone evaluation results were excellent in 16 patients and good in one, while functional results were excellent in 15 and good in two. The complication rate was 1.2 per patient. We conclude that acute shortening and distraction osteogenesis is a safe, reliable and successful method for the treatment of tibial nonunion with bone loss, with a shorter period of treatment and lower rate of complication.

Massive ovarian oedema in adolescents.

Massive ovarian oedema is an unusual clinical entity occurring in teenage girls. It is a rare tumour-like condition of the ovary characterized by marked enlargement of one or both ovaries due to marked accumulation of oedema fluid in the ovarian stroma. Massive ovarian oedema may result from partial or intermittent torsion of the mesovary, interfering with venous and lymphatic drainage, but not with arterial blood flow. The patients most commonly present with lower abdominal pain and enlargement. This entity can clinically mimic a neoplasia. We report three cases with massive ovarian oedema.

Prevalence and risk factors of low bone mineral density in patients with multiple sclerosis.

OBJECTIVES: To determine the prevalence and risk factors of low bone mineral density (BMD) in patients with multiple sclerosis (MS). METHODS: Patients with MS who had undergone a BMD evaluation via dual-energy X-ray absorptiometry (DXA) between January 2010 and December 2013 were included in the study. Descriptive data, BMD values, and risk factors for osteoporosis along with the details regarding MS, such as age at onset, duration of disease, clinical type of MS, expanded disability status scale (EDSS) scores, and lifetime steroid intake were obtained from the medical record database and telephone interview. RESULTS: The study group comprised 67 patients with a mean age of 41.1 ± 10.2 years. Of the patients, 20.9% revealed low BMD for chronological age. Vitamin D insufficiency (25(OH)D < 20  ng/ml) rate was 86.6%. Comorbidity and EDSS scores of patients with low BMD were significantly higher than those of the remaining patients (P = 0.000 and P = 0.015, respectively). Neck BMD was inversely correlated with comorbidity score, disease duration, relapse number, and lifetime steroid intake (r = - 0.270, r = - 0.263, r = - 0.359, and r = - 0.314, respectively). CONCLUSION: The current study revealed that low BMD and vitamin D insufficiency were common in patients with MS. Longer disease duration, higher comorbidity score, and severe disability level led to lower BMD values. In conclusion, it is of paramount importance for clinicians to pay more attention on bone health in MS and to tailor preventative measures meticulously.

Concordance of sexual dysfunction and dissatisfaction by self-report and those by partner's perception in young adult couples.

We evaluated concordance levels of young adult spouses (N=107 couples, total N=214) with regards to sexual satisfaction by using Golombock-Rust Inventory of Sexual Satisfaction (GRISS). Each spouse of the couples filled out both female and male forms of the GRISS. Self- and spouse-reported scores were analyzed in terms of inter-rater correlation and agreement. The prevalence of overall sexual dissatisfaction was 10.3% and 26.2% in wives and husbands, respectively. The correlation coefficient (r) between the self-reported overall sexual satisfaction scores and those assessed by the spouses was 0.25 (P=0.014) and 0.04 (P=0.680) for wives and husbands, respectively. The sensitivity for perception of partner's sexual problems ranged 11% to 47%, and the specificity was around 64% to 100%, except for vaginismus, which had a sensitivity of 83% and a specificity of 25%. The prevalance-adjusted and bias-adjusted kappa (PABAK) value for overall sexual dissatisfaction reported by themselves and that assessed by their spouses was 0.68 and 0.16 for the wives and husbands, respectively. For specific female sexual problems, the PABAK value was the highest in female dissatisfaction (0.81) followed by anorgasmia (0.78), female avoidance (0.44), vaginismus (0.44), infrequency (0.33), non-communication (0.14) and female nonsensuality (0.14). For specific male sexual problems, the PABAK value was the highest in male nonsensuality (1.00), followed by male dissatisfaction (0.78), infrequency (0.46), non-communication (0.42), male avoidance (0.36), impotence (0.27) and premature ejaculation (-0.04). Our findings suggested that in this clinical sample the partner's perception of sexual dysfunction and dissatisfaction did not correlate well with the subject's self-reported sexual problems, and generally male sexual problems were less correctly perceived by the partners than were female sexual problems. This result may provide helpful information for clinicians who take care of patients' sexual problems.