Primary urothelial carcinoma of the ureter without concurrent renal pelvic or bladder carcinoma: A contemporary clinicopathologic analysis.

Primary urothelial carcinoma (UCa) of the ureter is relatively uncommon, comprising less than 10% of all urinary tract tumors. Typically, ureteral UCa is found in association with other urinary tract tumors, such as renal pelvic or bladder UCa, making it challenging to analyze the clinicopathologic features in isolation. With only a few small case series and case reports available, our understanding of primary ureteral UCa is limited. Herein, we conducted one of the largest studies to date of primary ureteral UCa without concurrent renal pelvic or bladder UCa. Clinicopathologic parameters including extent of invasion, lymphovascular invasion, variant histology, presence of UCa in situ, inverted growth pattern, and clinical follow-up information were obtained. Ninety-seven cases were included in the study. Thirty-nine cases (40%) showed invasion, the preponderance of which invaded lamina propria (15%; 15/97), followed by periureteral soft tissue/adipose (14%; 14/97), muscularis propria (9%; 9/39), and seminal vesicle invasion (1%; 1/97). Clinical follow-up data was available for 80/89 (89%) patients with a mean duration of 35 months (range: 1-206 months). Metastatic UCa developed in 28/89 (35%) patients, 20/28 (71%) of which had invasive disease at presentation. Of the 17 (21%) patients who died, 12 (71%) initially presented with invasive UCa. Although more patients had non-invasive UCa, the propensity for worse outcomes in patients with invasive disease is greater compared to other urinary tract sites. These findings further emphasize the importance of early recognition of these tumors, in view of the relatively high preponderance of advanced disease and mortality in a subset of these patients.

A case report of COVID-19 associated pulmonary mucormycosis.

Hospitalized patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) are at risk for developing secondary fungal infections due to greater incidence of preexisting comorbidities and exposure to iatrogenic factors such as corticosteroid use. We present the case of a 44-year-old Hispanic female discovered unresponsive in her home that was found to have severe hyperglycemia with comorbid COVID-19 (coronavirus disease 2019) associated pneumonia. The patient was intubated and treated with several broad-spectrum antibiotics, remdesivir, and corticosteroids but had little improvement in her clinical status. Bronchoscopy was performed and revealed multiple necrotic lesions in the lungs. Endobronchial biopsy and bronchoalveolar lavage samples revealed pauciseptated hyphae consistent with zygomycetes. The patient was treated with multiple antifungals including voriconazole, micafungin, and amphotericin B. However, despite maximal medical therapy, the patient perished. This case highlights that clinicians must carry a high degree of suspicion and a low threshold to begin treatment for Mucor in diabetics and other immunosuppressed patients.

Invasive high-grade urothelial carcinoma of the bladder, renal pelvis, ureter, and prostatic urethra arising in a background of urothelial carcinoma with an inverted growth pattern: a contemporary clinicopathological analysis of 91 cases.

Urothelial carcinoma with an inverted/endophytic growth pattern can occasionally mimic inverted urothelial papilloma and pose diagnostic challenges when assessing the presence or absence of invasion. Making these distinctions is critical for guiding appropriate treatment and improving patient outcomes. Here we conducted one of the largest studies to date of invasive high-grade urothelial carcinoma arising in a background of urothelial carcinoma with an inverted growth pattern. Primary sites examined included bladder, renal pelvis, ureter, and prostatic urethra. Clinicopathological parameters including extent of invasion, variant histology, presence of urothelial carcinoma in situ, and clinical follow-up were obtained. Ninety-one cases from 82 patients were included in the study. Lamina propria invasion was present in 81% of bladder, 60% of ureter, 20% of renal pelvis, and 100% of prostatic urethra cases. Muscularis propria invasion was identified in 19% of bladder, 14% of ureter, and 20% of renal pelvis cases. Urothelial carcinoma invaded periureteric fat in 29% of ureter cases and invaded the renal parenchyma in 60% of renal pelvis cases. Clinical follow-up was available for 77 of 82 (94%) patients with a mean duration of 18 months. Recurrent urothelial carcinoma persisted in 63 of 82 (77%) patients, 16 of 82 (19%) progressed with metastatic disease, and 20 of 77 (26%) patients with bladder involvement died of disease. This study further emphasizes the importance of distinguishing these tumors from benign mimickers of urothelial carcinoma. Recognition of invasive foci is also critical in view of the potentially high frequency of recurrence and the possibility of advanced disease in a subset of these patients.

The Revolution in Medical Education.

Medical education has been gradually evolving for hundreds of years, but educators are now seeking to identify ways to prepare students for the future of health care delivery. Medical education reform today focuses on creating entirely new models and is moving away from the traditional, post-Flexnerian organization of the medical school curriculum. Content is now being integrated thematically and presented along interdisciplinary lines with an interdigitation of basic and clinical sciences across all four years. Current trends indicate education should contain elements that produce a physician who is able to improve the quality of health care by taking a humanistic approach to medicine, thinks critically, and participates effectively in multidisciplinary and team approaches to patient care. Ultimately, medical education innovation should recognize the development of a physician is a lifetime process and will approach the formation of physicians from a new paradigm to better serve the educator and prepare the learner for the medical practice of tomorrow.

A Breast Tissue Protein Expression Profile Contributing to Early Parity-Induced Protection Against Breast Cancer.

BACKGROUND/AIMS: Early parity reduces breast cancer risk, whereas, late parity and nulliparity increase breast cancer risk. Despite substantial efforts to understand the protective effects of early parity, the precise molecular circuitry responsible for these changes is not yet fully defined. METHODS: Here, we have conducted the first study assessing protein expression profiles in normal breast tissue of healthy early parous, late parous, and nulliparous women. Breast tissue biopsies were obtained from 132 healthy parous and nulliparous volunteers. These samples were subjected to global protein expression profiling and immunohistochemistry. GeneSpring and MetaCore bioinformatics analysis software were used to identify protein expression profiles associated with early parity (low risk) versus late/nulliparity (high risk). RESULTS: Early parity reduces expression of key proteins involved in mitogenic signaling pathways in breast tissue through down regulation of EGFR1/3, ESR1, AKT1, ATF, Fos, and SRC. Early parity is also characterized by greater genomic stability and reduced tissue inflammation based on differential expression of aurora kinases, p53, RAD52, BRCA1, MAPKAPK-2, ATF-1, ICAM1, and NF-kappaB compared to late and nulli parity. CONCLUSIONS: Early parity reduces basal cell proliferation in breast tissue, which translates to enhanced genomic stability, reduced cellular stress/inflammation, and thus reduced breast cancer risk.

Adherence to physical activity guidelines in older adults, using objectively measured physical activity in a population-based study.

BACKGROUND: Physical activity (PA) levels in older adults decline with age. The prevalence and correlates of adherence to current UK PA guidelines in older adults has not been studied using objectively measured PA, which can examine precisely whether PA is carried out in bouts of specified length and intensity. METHODS: Free living men and women aged 70-93 years from 25 towns in the United Kingdom, participating in parallel on-going population based cohort studies were invited (by post) to wear a GT3x accelerometer over the hip for one week in 2010-12. Adherence to UK PA guidelines was defined as ≥150 minutes/week of moderate or vigorous PA (MVPA) in bouts of ≥10 minutes; the effect of different intensities and durations were examined. RESULTS: 1593 men and 857 women participated (responses 51% and 29% respectively). 15% men and 10% women achieved ≥150 minutes/week of MVPA (defined as >1040 cpm) in bouts lasting ≥10 minutes. With MVPA defined as >1952 cpm, prevalences were 7% and 3% respectively. Those adhering to guidelines were younger, had fewer chronic health conditions, less depression, less severe mobility limitations, but higher exercise self-efficacy and exercise outcomes expectations. They rated their local environment more highly for social activities and leisure facilities, having somewhere nice to go for a walk and feeling safe after dark, They left the house on more days per week, were more likely to use active transport (cycle or walk) and to walk a dog regularly. CONCLUSIONS: Few older adults attain current PA guidelines. Health promotion to extend the duration of moderate-intensity activity episodes to 10 minutes or more could yield important health gains among older adults. However future studies will need to clarify whether attaining guideline amounts of PA in spells lasting 10 minutes or more is critical for reducing chronic disease risks as well as improving cardiometabolic risk factors.

Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis, and angiogenesis.

Plant-based medicines are useful in the treatment of cancer. Many breast cancer patients use complementary and alternative medicine in parallel with conventional treatments. Neem is historically well known in Asia and Africa as a versatile medicinal plant with a wide spectrum of biological activities. The experiments reported herein determined whether the administration of an ethanolic fraction of Neem leaf (EFNL) inhibits progression of chemical carcinogen-induced mammary tumorigenesis in rat models. Seven-week-old female Sprague Dawley rats were given a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Upon the appearance of palpable mammary tumors, the rats were divided into vehicle-treated control groups and EFNL-treated groups. Treatment with EFNL inhibited MNU-induced mammary tumor progression. EFNL treatment was also highly effective in reducing mammary tumor burden and in suppressing mammary tumor progression even after the cessation of treatment. Further, we found that EFNL treatment effectively upregulated proapoptotic genes and proteins such as p53, B cell lymphoma-2 protein (Bcl-2)-associated X protein (Bax), Bcl-2-associated death promoter protein (Bad) caspases, phosphatase and tensin homolog gene (PTEN), and c-Jun N-terminal kinase (JNK). In contrast, EFNL treatment caused downregulation of anti-apoptotic (Bcl-2), angiogenic proteins (angiopoietin and vascular endothelial growth factor A [VEGF-A]), cell cycle regulatory proteins (cyclin D1, cyclin-dependent kinase 2 [Cdk2], and Cdk4), and pro-survival signals such as NFκB, mitogen-activated protein kinase 1 (MAPK1). The data obtained in this study demonstrate that EFNL exert a potent anticancer effect against mammary tumorigenesis by altering key signaling pathways.

Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR.

Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.

Prediction of spontaneous preterm birth in asymptomatic twin pregnancies with the use of combined fetal fibronectin and cervical length.

OBJECTIVE: The purpose of this study was to evaluate combined fetal fibronectin (fFN) test result and cervical length (CL) as predictors of spontaneous preterm birth in asymptomatic twin pregnancies. STUDY DESIGN: We examined a retrospective cohort of 155 twin pregnancies with combined fFN and CL testing between 22 and 32 weeks gestation. RESULTS: A positive fFN test result at 22-32 weeks or a CL <20 mm increased the risk of spontaneous preterm birth at <37, <34, <32, <30, and <28 weeks' gestation. The combination of a positive fFN test result and CL<20 mm had a significantly higher positive predictive value for delivery at all gestational ages than either positive test alone. On adjusted analysis, a positive fFN test result was a stronger predictor of spontaneous preterm birth than a short CL. CONCLUSION: In asymptomatic twin pregnancies, fFN and CL testing between 22 and 32 weeks gestation can identify pregnancies that are at significantly increased risk for preterm birth, including deliveries at <28 weeks' gestation.

G protein betagamma subunits interact with alphabeta- and gamma-tubulin and play a role in microtubule assembly in PC12 cells.

The betagamma subunit of G proteins (Gbetagamma) is known to transfer signals from cell surface receptors to intracellular effector molecules. Recent results suggest that Gbetagamma also interacts with microtubules and is involved in the regulation of the mitotic spindle. In the current study, the anti-microtubular drug nocodazole was employed to investigate the mechanism by which Gbetagamma interacts with tubulin and its possible implications in microtubule assembly in cultured PC12 cells. Nocodazole-induced depolymerization of microtubules drastically inhibited the interaction between Gbetagamma and tubulin. Gbetagamma was preferentially bound to microtubules and treatment with nocodazole suggested that the dissociation of Gbetagamma from microtubules is an early step in the depolymerization process. When microtubules were allowed to recover after removal of nocodazole, the tubulin-Gbetagamma interaction was restored. Unlike Gbetagamma, however, the interaction between tubulin and the alpha subunit of the Gs protein (Gsalpha) was not inhibited by nocodazole, indicating that the inhibition of tubulin-Gbetagamma interactions during microtubule depolymerization is selective. We found that Gbetagamma also interacts with gamma-tubulin, colocalizes with gamma-tubulin in centrosomes, and co-sediments in centrosomal fractions. The interaction between Gbetagamma and gamma-tubulin was unaffected by nocodazole, suggesting that the Gbetagamma-gamma-tubulin interaction is not dependent on assembled microtubules. Taken together, our results suggest that Gbetagamma may play an important and definitive role in microtubule assembly and/or stability. We propose that betagamma-microtubule interaction is an important step for G protein-mediated cell activation. These results may also provide new insights into the mechanism of action of anti-microtubule drugs.

Macro-array and bioinformatic analyses reveal mycobacterial 'core' genes, variation in the ESAT-6 gene family and new phylogenetic markers for the Mycobacterium tuberculosis complex.

To better understand the biology and the virulence determinants of the two major mycobacterial human pathogens Mycobacterium tuberculosis and Mycobacterium leprae, their genome sequences have been determined recently. In silico comparisons revealed that among the 1439 genes common to both M. tuberculosis and M. leprae, 219 genes code for proteins that show no similarity with proteins from other organisms. Therefore, the latter 'core' genes could be specific for mycobacteria or even for the intracellular mycobacterial pathogens. To obtain more information as to whether these genes really were mycobacteria-specific, they were included in a focused macro-array, which also contained genes from previously defined regions of difference (RD) known to be absent from Mycobacterium bovis BCG relative to M. tuberculosis. Hybridization of DNA from 40 strains of the M. tuberculosis complex and in silico comparison of these genes with the near-complete genome sequences from Mycobacterium avium, Mycobacterium marinum and Mycobacterium smegmatis were undertaken to answer this question. The results showed that among the 219 conserved genes, very few were not present in all the strains tested. Some of these missing genes code for proteins of the ESAT-6 family, a group of highly immunogenic small proteins whose presence and number is variable among the genomically highly conserved members of the M. tuberculosis complex. Indeed, the results suggest that, with few exceptions, the 'core' genes conserved among M. tuberculosis H37Rv and M. leprae are also highly conserved among other mycobacterial strains, which makes them interesting potential targets for developing new specific anti-mycobacterial drugs. In contrast, the genes from RD regions showed great variability among certain members of the M. tuberculosis complex, and some new specific deletions in Mycobacterium canettii, Mycobacterium microti and seal isolates were identified and further characterized during this study. Together with the distribution of a particular 6 or 7 bp micro-deletion in the gene encoding the polyketide synthase pks15/1, these results confirm and further extend the revised phylogenetic model for the M. tuberculosis complex recently presented.

Extensive and divergent effects of sleep and wakefulness on brain gene expression.

Sleep is present in all species where it has been studied, but its functions remain unknown. To investigate what benefits sleep may bring at the cellular level, we profiled gene expression in awake and sleeping rats by using high-density microarrays. We find that approximately 10% of the transcripts in the cerebral cortex change their expression between day and night and demonstrate that half of them are modulated by sleep and wakefulness independent of time of day. We also show that molecular correlates of sleep are found in the cerebellum, a structure not known for generating sleep rhythms. Finally, we show that different functional categories of genes are selectively associated with sleep and wakefulness. The approximately 100 known genes whose expression increases during sleep provide molecular support for the proposed involvement of sleep in protein synthesis and neural plasticity and point to a novel role for sleep in membrane trafficking and maintenance.

[Orthotopic neobladder in a female patient after radiotherapy and anterior exenteration with ileal conduit]. / Neovejiga ortotópica en una paciente después de radioterapia y exenteración anterior con conducto ileal.

OBJECTIVE: To demonstrate the viability of a neobladder created after radiotherapy, anterior pelvic exanteration and previous ileal conduit. METHODS: We report the case of a female patient who underwent anterior pelvic exanteration, radiotherapy and ileal conduit as treatment for uterine cervix cancer. A transverse colon neobladder was performed and anastomosed to the urethral stump. It was also constructed an independent self-catheterizable conduct connected to the abdominal wall, with an adjacent segment of transverse colon using the Monti's technique. This was an alternative route for catheterization in the case of problems with the urethral anastomosis. RESULTS: Patient achieved complete continence but requires intermittent catheterization to empty her neobladder. Upper urinary tract has remained stable. The patient presented with urethral stenosis that required periodic dilations. The catheterizable conduit presented incontinence and obstruction problems due to granuloma formation and had to be removed. CONCLUSIONS: Undiversion with creation of a neobladder and urethral anastomosis is viable in female patient after radiotherapy. Urethral stenosis was an important complication.