Clinical Anatomy of the Superficial Preprostatic Vein and Accessory Pudendal Artery in Robot-Assisted Radical Prostatectomy.

Purpose: We herein describe the superficial preprostatic vein (SPV) anatomy and determine its relationship with the accessory pudendal artery (APA). Materials and Methods: We reviewed 500 patients with localized prostate cancer who underwent conventional robot-assisted radical prostatectomy between April 2019 and March 2023 at our institution. SPV was defined as "any vein coming from the space between the puboprostatic ligaments and running within the retropubic adipose tissue anterior to the prostate toward the vesical venous plexus or pelvic side wall." While APA was defined as "any artery located in the periprostatic region running parallel to the dorsal vascular complex and extending caudal toward the anterior perineum." The intraoperative anatomy of each SPV and APA was described. Results: SPVs had a prevalence rate of 88%. They were preserved in 252 men (58%) and classified as I-, reversed-Y (rY)-, Y-, or H-shaped (64%, 22%, 12%, and 2%, respectively) based on their intraoperative appearance. Overall, 214 APAs were found in 142 of the 252 men with preserved SPV (56%; 165 lateral and 50 apical APAs in 111 and 41 men, respectively). SPVs were pulsatile in 39% men perhaps due to an accompanying tiny artery functioning as a median APA. Pulsations seemed to be initially absent in most SPVs but become apparent late during surgery possibly due to increased arterial and venous blood flow after prostate removal. Pulsations were common in men with ≥1 APA. Conclusions: This study, which described the anatomical variations in arteries and veins around the prostrate and their preservation techniques, revealed that preserving this vasculature may help preserve postprostatectomy erection. ClinicalTrials: The Clinical Research Registration Number is 230523D.

Inguinal hernia leads to worse immediate urinary continence after robot-assisted radical prostatectomy.

OBJECTIVES: Patients with inguinal hernia (IH) may have voiding dysfunction and weak urethra-stabilizing periurethral fascial tissues, contributing to urinary incontinence. This study aimed to review the association between IH and urinary continence after robotic-assisted radical prostatectomy (RARP). METHODS: This single-institution retrospective study included 251 consecutive cases of RARP between April 2019 and June 2022. Patients with concurrent IH or a history of adult IH repair were examined. The urine loss rate (ULR), defined as 24-h urine loss volume divided by the total urine volume immediately after urinary catheter removal (i.e., 6 or 7 postoperative days), was compared between the groups with (n = 33) and without IH (n = 214). Possible contributing factors for ULR were assessed, including age, body mass index (BMI), after benign prostatic hyperplasia surgery, prostate weight, and nerve-sparing. ULR was compared intergroup after propensity score matching countering selection biases. RESULTS: Patients with IH were older (71.3 versus. 66.8 years, p < 0.01), had lower BMI (22.8 versus. 24.3, p < 0.01), and had higher ULR (14.5% versus. 5.1%, p < 0.01). In a multiple linear regression analysis (adjusted R2 = 0.084), IH (p < 0.01) was an independent contributing factor for ULR besides advancing age (p < 0.03). After propensity score matching adjusted for patient's age and nerve-sparing, patients with IH had higher ULR (14.1% versus. 5.7%, p < 0.03) as well. CONCLUSIONS: This study first reported that IH may be one of the risk factors of urinary incontinence after RARP.

[Laboratory Medicine Support for Disaster-Affected Region].

As natural disasters have been occurring more frequently in recent years, the need to prepare for a future disaster is growing. Based on the experience of the Great Hanshin earthquake occurred in 1995, we pre- dicted that laboratory test demand will be increased one week post-disaster. Also, the provision of medical and health care services is indispensable in areas affected by disasters for not only acute-phase patients, but also for those with diabetes, hypertension, and chronic diseases. This study summarized how laboratory medicine supplies were provided to the region affected by the Great East Japan earthquake occurred in 2011. In order to provide laboratory medicine supplies in the affected region, the Japanese Society of Laboratory Medicine set up a committee to respond to the Great East Japan earthquake as a temporary measure. Since electric power and water supplies are cut after a disaster, we decided to provide support using Point-Of-Care Testing (POCT) devices and disposable In-Vitro Diagnostic (IVD) reagents. A total of 40 companies agreed to provide support, and more than 100 IVD reagents were prepared. We posted the above information on our website, and updated it immediately when additional support requests were made. In addition, volunteer clinical technologists were sent to the affected region for 8 weeks, in order to support laboratory tests per- formed in temporary clinics or first aid stations. This experience was immediately applied to medical sup- port activities performed after the 2016 Kumamoto earthquake. This study identified the usefulness of la- boratory tests and clinical technologists in disaster-affected regions. [Review].

[Role of the POC Coordinator in Japan].

Point-of-care testing (POCT) is able to shorten the therapeutic turn around time (TTAT) because of its portability, proximity to the patient, and the use of rapid testing methodologies. These advantages are dependent on the quality of POCT procedures. It is recommended that all POCT instrumentation and operators conform to the hospital's POCT policy. There are two basic requirements necessary for high-quality POCT in a hospital setting. First is the proper management of all POCT instrumentation including reagents, and the second is training/competency assessment for all operators. This training should include the correct use of equipment, reagent requirements, and trouble-shooting any errors that might occur during testing. In many cases, POCT operators are not familiar with the importance of analytical quality management because of their lack of experience with laboratory techniques. However, users can improve their POCT ability and knowledge via the training/education program managed by the POCT department. The POC coordinator's role is to oversee that the proper procedure, based on the hospital's policy, is being followed. It is advised that the hospital form a POCT committee. The members should consist of at least: the Director of Laboratory Medicine, POC coordinator, a financial advisor, and several representative users from physicians and nursing staff. The POC coordinator will act as a representative of the POCT committee and work to maintain a quality program within the hospita/institution. In this article, we have summarized the role of the POC coordinator and the function of a POCT committee in a Japanese hospital.

En-Bloc Technique With Anteroposterior Dissection Holmium Laser Enucleation of the Prostate Allows a Short Operative Time and Acceptable Outcomes.

OBJECTIVE: To simplify anteroposterior dissection holmium laser enucleation of the prostate by combining it with a novel en-bloc enucleation technique that omits median lobe enucleation and removes the adenoma en-bloc in benign prostatic hyperplasia patients. METHODS: Between September 2013 and May 2014, 65 patients with benign prostatic hyperplasia underwent holmium laser enucleation of the prostate with the en-bloc technique we developed at our institution. Twenty-six patients who underwent surgery performed by the same experienced surgeon were included in our study. We evaluated the surgical parameters, including total operative time, enucleation time, morcellation time, and hemoglobin loss. Peak flow rate and postvoid residual urine volume were assessed 3 months postoperatively, and urinary incontinence was assessed 1 day after catheter removal and at 1 and 3 months postoperatively in all patients. RESULTS: Mean total operating time and mean enucleation time were 56.4 and 26.5 minutes, respectively. Peak flow rate and postvoid residual urine volume significantly improved. The incidence of postoperative incontinence at 3 months was 3%. CONCLUSION: Our en-bloc enucleation method required a short operating time and may address concerns regarding the complexity of the enucleation procedure. We believe the incidence of postoperative incontinence can be further reduced with additional refinements of this procedure.

[Activities for laboratory medicine support after the Great East Japan Earthquake by the Japanese Society of Laboratory Medicine].

The Great East Japan Earthquake caused a tragic tsunami and resulted in serious damage to north region of Japan on March 11, 2011. The Japanese Society of Laboratory Medicine, JSLM launched an ad hoc Committee to support Laboratory Medicine affairs in the affected area. We expected that laboratory testing demands would increase during the weeks following the disaster. We decided to support the use of Point-of-Care Testing. Many POCT devices use battery-powered analyzers. This is definite advantage for their use in areas with limited access to power and water supplies. We contacted many companies about the possibility of providing POCT devices, IVD reagents and/or any laboratory supplies including disposable materials. Finally, forty companies agreed to support this project and we received list of reagents materials for more than one hundred IVD tests. We entered this information on our web site and continued to update it as additional support was received. Once a request of support was received, communication were made to confirm the amount of material, the method of shipping/receipt and if any specific training that would be required for its use at the testing site. Also, we dispatched volunteer Medical Technologists for eight weeks to assist in the laboratory work. Some of the crucial points in recruiting volunteer laboratory professions are expenses and accommodations. We prepared not only accommodations but also transportation methods and covered all expenses including insurance and meals. Our relief activities have shown that Laboratory Medicine and Medical Technologists are useful in disaster-affected area.

Cytokeratin 18 expression inhibits cytokine-induced death of cervical cancer cells.

OBJECTIVES: In cervical cancer, increased cytokeratin 18 (CK18) filament expression is associated with disease progression. However, it may also provide resistance to cytokine-induced apoptosis. The present study tested whether CK18 expression influences susceptibility to cytokine-induced apoptosis. METHODS: The cervical cancer cell lines C-4II (high CK18 expression), ME-180 (low CK18 expression), and 2 subtypes of HeLa cells containing or lacking CK18 expression (CK18+ and CK18- cells, respectively) were exposed to vehicle (control), Fas ligand (FasL) (50 ng/mL), or tumor necrosis factor α (TNF-α; 10 ng/mL) without/with cycloheximide (CHX; 2.5 µg/mL) to test the hypothesis that diminished CK18 expression increases susceptibility to cytokine-induced apoptosis. RESULTS: Flow cytometric analysis of cell death via TUNEL staining revealed that cytokine-induced apoptosis was 2-fold greater in ME-180 cells than C-4II cells in response to FasL+CHX or TNF-α+CHX (P < 0.05). Similarly, there was a higher incidence of FasL-induced apoptosis in CK18- HeLa cells (23% and 91% apoptotic for FasL and FasL+CHX, respectively) than CK18+ HeLa cells (1% and 11%, respectively; P < 0.05). Surprisingly, TNF-α had no effect on either CK18+ or CK18- HeLa cells (P > 0.05). Caspase 3 activity was greater in CK18- HeLa cells than in CK18+ HeLa cells at 8 and 18 hours after FasL treatment (P < 0.05), an effect abrogated by the caspase 8 inhibitor IETD-fmk (P < 0.05). CONCLUSIONS: Cervical cancer cells with diminished CK18 expression are more susceptible to cytokine-induced apoptosis, particularly in response to FasL treatment. These observations suggest that relative CK18 expression is an important factor when considering therapeutic strategies to enhance immune cell-mediated death of cervical cancer cells.

ABCC10/MRP7 is associated with vinorelbine resistance in non-small cell lung cancer.

The non-small cell lung cancer (NSCLC) cells SK-LC6 and NCI-H23 were continuously exposed to vinorelbine (VNB), and the VNB-resistant clones, SK-LC6/VNB and H23/VNB were selected. Since SK-LS6/VNB and H23/VNB cells showed cross-resistance to certain anticancer drugs, such as paclitaxel and docetaxel, we examined the gene expression levels of drug efflux transporters of the ATP-binding cassette (ABC) family. We found that the gene expression of ABCB1/MDR1 and ABCC10/MRP7 in SK-LC6/VNB and H23/VNB cells was increased compared with that in SK-LS6 and NCI-H23 cells, whereas the expression of ABCC1/MRP1, ABCC2/MRP2, ABCC3/MRP3 and ABCG2/BCRP did not change among these cells. Treatment with ABCB1/MDR1 inhibitor verapamil and ABCC10/MRP7 inhibitor sulfin-pyrazone altered the sensitivity of SK-LC6/VNB cells to vinorelbine. To confirm the ABCC10/MRP7 activity, we transfected small interfering RNA against ABCC10/MRP7 to ABCC10/MRP7-expressing RERF-LC-AI cells resulting in the decrease of ABCC10/MRP7 expression concomitant with the alteration of VNB cytotoxicity. Moreover, we detected the expression of ABCC10/MRP7 in 12 of 17 NSCLC cells, whereas ABCB1/MDR1 was detected in only 3 of 17 NSCLC cells. These results indicate that ABCC10/MRP7 may confer VNB resistance in NSCLC.

Does a clinical varicocele influence the relationship between testicular volume by ultrasound and testicular function in patients with infertility?

OBJECTIVE: To determine whether varicocele influences the testicular volume-function relationship. DESIGN: Retrospective clinical study. SETTING: University hospital. PATIENT(S): One hundred fifty infertile patients with varicocele and 299 without varicocele. INTERVENTION(S): Semen analyses, scrotal ultrasound, and serum FSH, LH, and T levels. MAIN OUTCOME MEASURE(S): The mean testicular volume was measured by ultrasound. To evaluate the testicular volume-function relationship in infertile patients with varicocele and in those without varicocele, the patients were divided into seven and 10 groups, respectively, according to the mean testicular volume. RESULT(S): The semen density, total sperm count, and serum FSH levels significantly correlated with the mean testicular volume in both patient groups, but patients without varicocele had a greater correlation coefficient than those with varicocele. The mean testicular volume with mean sperm densities indicating oligozoospermia was greater in the patients with varicocele than in patients without varicocele (12.5 and 10.0 mL, respectively). The mean testicular volume with mean FSH concentration exceeding the normal range was higher in patients with varicocele (15.0 mL) than in patients without varicocele (12.5 mL). CONCLUSION(S): The testicular volume-function correlation differed between patients with varicocele and those without varicocele. The presence of varicocele therefore influences the relationship between the testicular volume and the testicular function.

Is varicocele associated with underlying venous abnormalities? Varicocele and the prostatic venous plexus.

PURPOSE: We examined the pampiniform plexus and prostatic venous plexus using color Doppler ultrasonography and evaluated the relationship between varicocele and the prostatic venous plexus. MATERIALS AND METHODS: This study included 209 men with a mean age of 35.3 years, of whom 68 had no varicoceles, 94 had a unilateral varicocele and 47 had bilateral varicoceles based on scrotal color Doppler ultrasonography. The diameter of the pampiniform plexus and prostatic venous plexus was measured using scrotal and transperineal ultrasonography, respectively. Peak retrograde and antegrade flow velocity of the prostatic venous plexus was measured by transperineal color Doppler ultrasonography. RESULTS: Mean diameter, and peak and antegrade flow velocity of the prostatic venous plexus were greater in men with bilateral varicoceles than in those with a unilateral varicocele and in those without a varicocele (p <0.01). Moreover, men with a unilateral varicocele had a greater mean peak antegrade flow velocity than those without a varicocele (p <0.05). However, mean diameter and peak retrograde flow velocity were not different in men with a unilateral varicocele and those without a varicocele. In 10 men with a left clinical varicocele mean diameter, and peak retrograde and antegrade flow velocity of the prostatic venous plexus did not differ before vs after varicocele repair. In all men the diameter of the prostatic venous plexus positively correlated with the diameter of the right and left pampiniform plexus (p <0.0001). CONCLUSIONS: Varicocele, especially bilateral varicoceles, may be associated with underlying venous abnormalities.

Traumatic bilateral testicular dislocation: a recovery of spermatogenesis by orchiopexy 15 years after the onset.

OBJECTIVE: To report a patient with azoospermia who achieved an induction of spermatogenesis after undergoing orchiopexy of long-standing bilateral traumatic dislocated testes. DESIGN: Case report. SETTING: Clinical. PATIENT(S): A 33-year-old man. INTERVENTION(S): Imaging studies, orchiopexy, testicular biopsy, and a review of similar cases. MAIN OUTCOME MEASURE(S): Recovery of spermatogenesis after orchiopexy. RESULT(S): A patient with azoospermia with bilateral traumatic dislocated testes due to a motorcycle accident 15 years previously. A bilateral testicular dislocation in the superficial inguinal pouch was diagnosed by palpation, imaging studies, and exploration. A recovery of spermatogenesis was obtained after performing orchiopexy of bilateral dislocated testes. CONCLUSION(S): The recovery of spermatogenesis in patients with azoospermia with a bilateral testicular dislocation therefore may be successfully obtained after appropriately performing orchiopexy.

Relationship between testicular size by ultrasonography and testicular function: measurement of testicular length, width, and depth in patients with infertility.

OBJECTIVES: The relationships between simple testicular sizes, including the testicular length, width, and depth and testicular function were evaluated to determine the usefulness of measuring these simple parameters. METHODS: The mean of right and left testicular length, width and depth were measured in 408 men with infertility (mean age, 35.9 +/- 5.3 years) using ultrasonography. The ultrasonographic testicular volumes were calculated as the length x width x depth x 0.71. To evaluate the relationship between the testicular size and function, the patients were divided into seven to ten groups according to each testicular size parameter. RESULTS: The mean testicular volume, length, depth, and width were 13.4 ml, 3.86 cm, 1.80 cm, and 2.59 cm, respectively. These three testicular dimensions significantly correlated with sperm density, total sperm count, total motile sperm count, serum follicle-stimulating hormone and luteinizing hormone equal to ultrasonographic testicular volume. The mean sperm density was in the oligozoospermic range in patients with a mean testicular volume below 10 ml, a mean length below 3.5 cm, a mean depth below 1.75 cm, and a mean width below 2.5 cm. The mean total sperm count was subnormal in patients with a mean testicular volume below 10 ml, a mean length below 3.5 cm, a mean depth below 1.5 cm, and a mean width below 2.25 cm. CONCLUSIONS: The testicular length, width, and depth measured by ultrasonography significantly correlated with the testicular function as well as the ultrasonographic testicular volume. A simple measurement of the testicular length, width, and depth is useful for evaluating the testicular function.

Effects of varicocele repair in adults on ultrasonographically determined testicular volume and on semen profile.

OBJECTIVES: We determined the effect of varicocele repair on testicular volume according to scrotal ultrasonography, reported to provide the best approximation of actual testicular volume. METHODS: Forty-four men with left varicocele (mean age +/- standard deviation, 33.4 +/- 5.4 years) underwent varicocele repair. We performed both scrotal ultrasonography with color Doppler imaging and semen analysis before and after varicocele repair. Among these patients, 19 had a clinical left varicocele, 22 had clinical left and subclinical right varicoceles, and 3 had clinical left and right varicoceles. We calculated testicular volumes using the formula: Length x Width x Height x 0.71. RESULTS: For all 44 patients, mean left and total testicular volume improved significantly after varicocele repair (increases of 1.5 and 2.4 mL, respectively) as did semen profile data such as sperm per unit volume and percentage of motile sperm. In the 19 men with a clinical left varicocele, mean left testicular volume increased significantly (by 1.5 mL) after left varicocele repair, in association with increases in sperm per unit volume and motility percentage. In the 25 men with clinical left varicocele plus a subclinical or clinical right varicocele, mean left and total testicular volume improved significantly after repair of right and left varicoceles (increases of 1.5 and 2.7 mL, respectively). However, right testicular volume showed no significant increase in any patient group. CONCLUSIONS: Varicocele repair in adults with a clinical left varicocele increased left testicular volume and improved semen profiles.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation associated with a congenital bilateral absence of vas deferens.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations associated with cystic fibrosis have been reported to be rare in Japanese patients with congenital bilateral absence of vas deferens (CBAVD). A 28-year-old Japanese male was referred for infertility. Vas deferens and epididymis were not palpable bilaterally. Semen analyses showed azoospermia with volumes below 2.0 ml. Serum follicle-stimulating hormone value was slightly elevated. Seminal fructose concentration was also very low. Scrotal ultrasonography showed absence of the bodies and tails of the right and left epididymides. Imaging studies showed cystic dysplasia of the right seminal vesicle and agenesis of the left seminal vesicle. A CFTR gene mutation of I556V was found. Recent studies show that prevalence of CFTR gene mutation in Japanese CBAVD patients may be approximately equal to that of the Caucasian population. Genetic counselling may be recommended for any couple attempting assisted reproduction technology when the man has CBAVD.

Relationship between testicular volume and varicocele in patients with infertility.

OBJECTIVES: We evaluated the relationship between varicocele and testicular volume determined by ultrasonography in infertile men. METHODS: This study included 432 age-matched infertile men, 17 fertile men without scrotal abnormalities, and 20 fertile men with left clinical varicocele. The percentage testicular volume difference (%) between the right and left testicles was calculated as (right testicular volume - left testicular volume) x 100/right testicular volume. RESULTS: Of 432 infertile men, 91 had a left clinical varicocele, 32 had left clinical and right subclinical varicoceles, 9 had bilateral clinical varicoceles, 51 had a left subclinical varicocele, 22 had bilateral subclinical varicoceles, 8 had a right subclinical varicocele, and 219 had no varicocele. The relative decrement in left testicular volume compared with right testicular volume was not restricted to patients with varicocele. The presence of right subclinical varicocele did not influence absolute or percentage testicular volume differences in patients with left clinical or subclinical varicocele. Fertile patients with left clinical varicocele had larger absolute and percentage testicular volume differences than patients with infertility and fertile patients without scrotal abnormalities. However, infertile patients with left clinical varicocele, irrespective of the presence of right subclinical varicocele, had larger absolute and percentage testicular volume differences than infertile patients without varicocele, and more frequently had 15% to 30% testicular volume differences than those without varicocele. CONCLUSIONS: Left clinical testicular varicocele is associated with relative ipsilateral testicular hypotrophy in infertile patients. However, a subclinical varicocele was not important in determining differences between right and left testicular volumes.

Relationship between testicular volume and testicular function: comparison of the Prader orchidometric and ultrasonographic measurements in patients with infertility.

AIM: To evaluate the relationship between testicular function and testicular volume measured by using Prader orchidometry and ultrasonography (US) to determine the critical testicular volume indicating normal testicular function by each method. METHODS: Total testicular volume (right plus left testicular volume) was measured in 794 testes in 397 men with infertility (mean age, 35.6 years) using a Prader orchidometer and also by ultrasonography. Ultrasonographic testicular volumes were calculated as length X width X height X 0.71. To evaluate volume-function relationships, patients were divided into 10 groups representing 5-mL increments of total testicular volume by each method from below 10 mL to 50 mL or more. RESULTS: Mean total testicular volume based on Prader orchidometry and US were 36.8 mL and 26.3 mL, respectively. Semen volume, sperm density, total sperm count, total motile sperm count, and serum FSH, LH, and testosterone all correlated significantly with total testicular volume measured by either method. Mean sperm density was in the oligozoospermic range in patients with total testicular volume below 35 mL by orchidometry or below 20 mL by ultrasonography. Mean total sperm count was subnormal in patients with total testicular volume below 30 mL by orchidometry or under 20 mL by ultrasonography. CONCLUSION: Testicular volume measured by either ultrasonography or Prader orchidometry correlated significantly with testicular function. However, critical total testicular volume indicating normal or nearly normal testicular function was 30 mL to 35 mL using Prader orchidometer and 20 mL using ultrasonography. Prader orchidometry morphometrically and functionally overestimated the testicular volume in comparison to US.

Mechanisms of Cables 1 gene inactivation in human ovarian cancer development.

Cables 1, a cyclin-dependent kinase binding protein, is primarily involved in cell cycle regulation. Loss of nuclear Cables 1 expression is observed in human colon, lung and endometrial cancers. We previously reported that loss of nuclear Cables 1 expression was also observed with high frequency in a limited sample set of human ovarian carcinomas, although the mechanisms underlying loss of nuclear Cables 1 expression remained unknown. Our present objective was to examine Cables 1 expression in ovarian cancer in greater detail, and determine the predominant mechanisms of Cables 1 loss. We assessed potential genetic and epigenetic modifications of the Cables 1 locus through analyses of mutation, polymorphisms, loss of heterozygosity and DNA methylation. We observed a marked loss of nuclear Cables 1 expression in serous and endometrioid ovarian carcinomas that correlated with decreased Cables 1 mRNA levels. Although we detected no Cables 1 mutations, there was evidence of LOH at the Cables 1 locus and epigenetic modification of the Cables 1 promoter region in a subset of ovarian carcinomas and established cancer cell lines. From a functional perspective, over-expression of Cables 1 induced apoptosis, whereas, knockdown of Cables 1 negated this effect. Together these findings suggest that multiple mechanisms underlie the loss of Cables 1 expression in ovarian cancer cells, supporting the hypothesis that Cables 1 is a tumor suppressor in human ovarian cancer.

The Cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer.

Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Cables expression was reduced in 65% of primary CRCs. No mutations were detected in 10 exons of Cables in 20 primary colon tumors. Cables promoter was methylated in cell lines with decreased Cables expression and vice versa. 5-Aza-2'-deoxycytidine resulted in increased Cables expression in methylated cell lines. There was a significant correlation between promoter methylation and Cables gene expression in primary colon tumors. Sixty-five percent of primary colon tumors demonstrated chromosome 18q LOH. LOH involving the Cables region was observed in 35% of cases, including those in which more distal portions of chromosome 18q were retained, and Cables expression was decreased in all such cases. Loss of Cables expression in 65% of CRCs suggests that it is a common event in colonic carcinogenesis, with promoter methylation and LOH appearing to be important mechanisms of Cables gene inactivation.

Loss of CABLES1, a cyclin-dependent kinase-interacting protein that inhibits cell cycle progression, results in germline expansion at the expense of oocyte quality in adult female mice.

Recent studies have shown that cell cycle inhibitors encoded by the Ink4a gene locus constrain the self-renewing activity of adult stem cells of the hematopoietic and nervous systems. Here we report that knockout (KO) of the Cables1 [cyclin-dependent kinase (CDK)-5 and ABL enzyme substrate 1] cell cycle-regulatory gene in mice has minimal to no effect on hematopoietic stem cell (HSC) dynamics. However, female Cables1-null mice exhibit a significant expansion of germ cell (oocyte) numbers throughout adulthood. This is accompanied by a dramatic elevation in the number of atretic immature oocytes within the ovaries and an increase in the incidence of degenerating oocytes retrieved following superovulation of CABLES1-deficient females. These outcomes are not observed in mice lacking p16INK4a alone or both p16INK4a and p19ARF. These data support recent reports that adult female mice can generate new oocytes and follicles but the enhancement of postnatal oogenesis by Cables1 KO appears offset by a reduction in oocyte quality, as reflected by increased elimination of these additional germ cells via apoptosis. This work also reveals cell lineage specificity with respect to the role that specific CDK-interacting proteins play in restraining the activity of adult germline versus somatic stem cells.